Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies
Open accessAbstract
Transposable elements, known colloquially as 'jumping genes', constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. Here we utilize Drosophila melanogaster and postmortem human brain samples to identify transposable element dysregulation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologically characterized by deposits of tau protein in the brain. Mechanistically, we find that heterochromatin decondensation and reduction of piwi and piRNAs drive transposable element dysregulation in tauopathy. We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements in human Alzheimer's disease and progressive supranuclear palsy, suggesting that transposable element dysregulation is conserved in human tauopathy. Taken together, our data identify heterochromatin decondensation, piwi and piRNA depletion and consequent transposable element dysregulation as a pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.
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37 of 52 cited sources checked · 23 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Tau-induced decondensation of constitutive heterochromatin is a key event that mediates neuronal death in tauopathy.
“We have previously identified tau-induced decondensation of constitutive heterochromatin as a key event that mediates neuronal death in tauopathy10.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
- Premisecitation
Activation of the cell cycle in neurons is sufficient to induce neuronal death.
“Studies in Drosophila indicate that cell cycle activation is causal for neuronal death in tauopathy, and that activation of the cell cycle in neurons is sufficient to induce neuronal death18.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006). source
- Premisecitation
Expression of human wild-type or R406W mutant tau involves the same major mechanisms of tau-induced neurotoxicity in Drosophila models.
“Multiple previous studies report that expression of human wild-type or R406W mutant tau involve the same major mechanisms of tau-induced neurotoxicity in Drosophila models10,16,20.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
The Results section on chromatin structure reports that both wild-type and R406W tau reduce H3K9me2 and HP1α in Drosophila, supporting a shared heterochromatin-loss mechanism. The paper does not establish that the two forms involve the same major mechanisms of neurotoxicity more broadly; most subsequent mechanistic experiments use R406W tau. No page number is available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [16] Frost, B., Bardai, F. H. & Feany, M. B. Lamin dysfunction mediates neurodegeneration in tauopathies. Curr. Biol. 26, 129–136 (2016). source
The Results (page not provided) show that both wild-type and R406W tau reduce Lamin levels and cause Lamin invagination in Drosophila, supporting a shared pathway of toxicity. The paper does not establish that the two forms involve the same major mechanisms overall; its subsequent mechanistic experiments use R406W tau. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [20] Bardai, F. H. et al. A conserved cytoskeletal signaling cascade mediates neurotoxicity of FTDP-17 tau mutations in vivo. J. Neurosci. 38, 108–119 (2018). source
- Premisecitation
Tau-induced heterochromatin relaxation plays a causal role in mediating neurodegeneration.
“Tau-induced heterochromatin relaxation plays a causal role in mediating neurodegeneration, as loss of function mutations in Su(var)20533 and Su(var)3-934, genes encoding heterochromatin protein 1 (HP1) and a histone 3, lysine 9 methyltransferase, respectively, further deplete constitutive heterochromatin in tau transgenic Drosophila and enhance tau-induced neuronal death10.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
- Premisecitation
Cell cycle activation is causal for neuronal death in tauopathy in Drosophila.
“Studies in Drosophila indicate that cell cycle activation is causal for neuronal death in tauopathy, and that activation of the cell cycle in neurons is sufficient to induce neuronal death18.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006). source
- Premisecitation
Widespread relaxation of constitutive heterochromatin occurs in postmortem brains from patients with Alzheimer's disease and in Drosophila and mouse models of tauopathy.
“We have previously reported widespread relaxation of constitutive heterochromatin, a form of hyper-condensed DNA, in postmortem brains from patients with Alzheimer’s disease, which is the most common tauopathy, and in Drosophila and mouse models of tauopathy10.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
- Premisecitation
A causal association between HERV-K and neuronal dysfunction has previously been established, as ectopic expression of HERV-K or the retroviral envelope protein decreases synaptic activity and induces progressive motor dysfunction in mice.
“A causal association between HERV-K and neuronal dysfunction has previously been established, as ectopic expression of HERV-K or the retroviral envelope protein that it encodes decreases synaptic activity and induces progressive motor dysfunction in mice8”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl. Med. 7, 307ra153 (2015). source
The Results section (“HERV-K env transgenic animals develop motor dysfunction”; page not supplied) reports progressive motor dysfunction and a decrease in spontaneous excitatory postsynaptic current amplitude in mice expressing HERV-K env. It does not show those outcomes in mice expressing the entire HERV-K genome; the Results section reports whole-genome expression only in human neuronal cultures. “Decreases synaptic activity” is also broader than the specific synaptic measure that fell. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Anti-retroviral reverse transcriptase inhibitors inhibit HERV-K activation in cultured cells.
“Anti-retroviral reverse transcriptase inhibitors inhibit HERV-K activation in cultured cells43”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [43] Tyagi, R., Li, W., Parades, D., Bianchet, M. A. & Nath, A. Inhibition of human endogenous retrovirus-K by antiretroviral drugs. Retrovirology 14, 21 (2017). source
The Results section, “Inhibition of HERV-K by HIV-1 RT inhibitors” (page not available), reports that abacavir and zidovudine reduced HERV-K production in cultured HeLa cells after infection with pseudotyped HERV-K. This supports inhibition in cultured cells, but the experiment tested infection and viral production, not activation of endogenous HERV-K. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
Double stranded RNAs produced by transposable element transcripts, including HERVs, can trigger a type I interferon response through the innate immune system.
“double stranded RNAs produced by transposable element transcripts, including HERVs, can trigger a type I interferon response through the innate immune system44”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [44] Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016). source
The passages labeled Abstract describe ERV-derived enhancers that regulate genes after interferon stimulation, not double-stranded RNA produced by transposable-element transcripts triggering interferon production. Searches for double-stranded RNA, ERV transcripts, and innate immune sensing found no passage in our copy addressing that mechanism. (LLM, conf=0.77)
Experimental — accuracy not yet measured
- Findingown data
Pathogenic tau causes active transposable element mobilization in neurons.
“and demonstrate that pathogenic tau causes active transposable element mobilization in neurons.”
Quote in the paperSubstantial claim - Findingown data
The endogenous retrovirus class of transposable elements is increased in human tauopathy, including Alzheimer's disease and progressive supranuclear palsy.
“and find that the endogenous retrovirus class of transposable elements is increased in the context of human tauopathy.”
- Also stated in: § Abstract · plain
“We further report a significant increase in transcripts of the endogenous retrovirus class of transposable elements in human Alzheimer’s disease and progressive supranuclear palsy”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Transposable elements are differentially expressed in postmortem human brain tissue from patients with Alzheimer's disease and progressive supranuclear palsy.
“Using a systematic, unbiased approach, we identify transposable elements that are differentially expressed in postmortem human brain tissue from patients with Alzheimer’s disease and progressive supranuclear palsy, a “primary” tauopathy”
Quote in the paperSubstantial claim - Findingown data
Human tau expression in the adult Drosophila brain significantly alters levels of transposable element transcripts.
“Beginning with a simple model of tauopathy in Drosophila melanogaster11, we report significantly altered levels of transposable element transcripts as a consequence of human tau expression in the adult brain.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Wittmann, C. W. et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711–714 (2001). source
- Findingown data
Pan-neuronal piwi knockdown is sufficient to elevate transcript levels of most of the transposable elements that are increased in tauR406W transgenic Drosophila.
“These data indicate that pan-neuronal piwi knockdown (Supplementary Fig. 4a) is sufficient to elevate transcript levels of most of the transposable elements that are increased in tauR406W transgenic Drosophila (Fig. 3d), suggesting that tau-induced reduction of piwi and piRNAs is a major contributor to the transposable element expression profile in brains of tau transgenic Drosophila.”
Quote in the paperSubstantial claim - Findingown data
The significant increase in transposable element mobilization in tauopathy compared to controls is sustained in 40-day-old adults.
“The significant increase in transposable element mobilization in tauopathy compared to controls is sustained in 40-day-old adults (Fig. 4a, b).”
Quote in the paperSubstantial claim - Findingown data
Heterozygous loss of flamenco function exacerbates tau-induced activation of the cell cycle in neurons.
“We find that heterozygous loss of flamenco function exacerbates tau-induced activation of the cell cycle in neurons based on staining with an antibody recognizing proliferating cell nuclear antigen (PCNA) (Fig. 2c).”
Quote in the paperSubstantial claim - Findingown data
Heterozygous loss-of-function alleles of flamenco significantly enhance neuronal death in tauR406W transgenic Drosophila.
“Two different heterozygous loss of function alleles of flamenco23,24 do not induce neuronal death or locomotor deficits in controls, but significantly enhance neuronal death in tauR406W transgenic Drosophila (Fig. 2a) and exacerbate tau-induced locomotor deficits (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
No transposable element mobilization is detected in tauV337M transgenic Drosophila based on either gypsy-TRAP GFP reporter fluorescence or immunoblotting at day one of adulthood.
“Accordingly, we do not detect transposable element mobilization in tauV337M transgenic Drosophila based on either gypsy-TRAP GFP reporter fluorescence or immunoblotting at day one of adulthood, but detect a significant increase of transposable element mobilization in tau transgenic Drosophila based on both GFP fluorescence and immunoblotting at day ten of adulthood.”
Quote in the paperNot a substantial claim - Findingown data
RNAi-mediated piwi knockdown using two different non-overlapping RNAi lines is semi-lethal in the context of transgenic tau expression.
“RNAi-mediated piwi knockdown using two different non-overlapping RNAi lines is semi-lethal in the context of transgenic tau expression.”
Quote in the paperSubstantial claim - Findingown data
RNA-seq and NanoString analyses demonstrate that pathogenic tau disrupts baseline levels of transposable element transcripts in the brain.
“RNA-seq and NanoString analyses clearly demonstrate that pathogenic tau disrupts baseline levels of transposable element transcripts in the brain.”
Quote in the paperSubstantial claim - Findingown data
Pan-neuronal piwi reduction is sufficient to activate the cell cycle in neurons.
“Based on PCNA staining, pan-neuronal piwi reduction is also sufficient to activate the cell cycle in neurons (Supplementary Fig. 4b), suggesting that pathogenic tau acts through piwi reduction to mediate aberrant cell cycle activation and consequent neuronal death.”
Quote in the paperSubstantial claim - Findingown data
The most abundant class of differentially expressed transposable elements in tauopathy are Class I long terminal repeat retrotransposons.
“The most abundant class of differentially expressed elements in tauopathy are Class I long terminal repeat (LTR) retrotransposons, despite the fact that the majority of transposable elements in Drosophila are classified as Class II DNA transposons”
Quote in the paperNot a substantial claim - Findingown data
In the absence of tau, piwi knockdown is sufficient to induce neuronal death by day 10 of adulthood.
“In the absence of tau, piwi knockdown is sufficient to induce neuronal death by day 10 of adulthood (Fig. 3e).”
Quote in the paperSubstantial claim - Findingown data
Pan-neuronal piwi overexpression significantly reduces neuronal death in tau transgenic Drosophila.
“In further support of piwi reduction as a causal contributor to tau-induced neurotoxicity, pan-neuronal piwi overexpression significantly reduces neuronal death in tau transgenic Drosophila (Fig. 3g) without affecting total levels of transgenic tau protein (Supplementary Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
56% of the transposable element transcripts that are significantly increased in tau transgenic Drosophila are full-length Class I retrotransposons that are fully capable of mobilization.
“56% of the transposable element transcripts that are significantly increased in tau transgenic Drosophila are full-length Class I retrotransposons that are fully capable of mobilization.”
Quote in the paperSubstantial claim - Findingown data
Heterozygous loss-of-function alleles of flamenco exacerbate tau-induced locomotor deficits.
“Two different heterozygous loss of function alleles of flamenco23,24 do not induce neuronal death or locomotor deficits in controls, but significantly enhance neuronal death in tauR406W transgenic Drosophila (Fig. 2a) and exacerbate tau-induced locomotor deficits (Fig. 2b).”
Quote in the paperSubstantial claim - Findingown data
Genetically promoting heterochromatin relaxation by loss-of-function mutations in Su(var)205 or Su(var)3-9 causes an increase in most of the transposable element transcripts that were identified as significantly increased in tau transgenic Drosophila based on RNA-seq.
“NanoString analyses reveal that genetically promoting heterochromatin relaxation by loss of function mutations in Su(var)205 or Su(var)3-9 causes an increase in most of the transposable element transcripts that were identified as significantly increased in tau transgenic Drosophila based on RNA-seq (Supplementary Fig. 5a, b).”
Quote in the paperSubstantial claim - Findingown data
Piwi overexpression does not affect total levels of transgenic tau protein.
“In further support of piwi reduction as a causal contributor to tau-induced neurotoxicity, pan-neuronal piwi overexpression significantly reduces neuronal death in tau transgenic Drosophila (Fig. 3g) without affecting total levels of transgenic tau protein (Supplementary Fig. 4c).”
Quote in the paperSubstantial claim - Findingown data
Small RNA sequencing revealed a significant decrease in 46 of 50 differentially expressed piRNAs in heads of tau transgenic Drosophila at day 10 of adulthood.
“Small RNA sequencing revealed a significant decrease in 46 of 50 differentially expressed piRNAs in heads of tau transgenic Drosophila at day 10 of adulthood (Fig. 3a, Supplementary Table 5, 6).”
Quote in the paperSubstantial claim - Findingown data
Flamenco mutations do not affect total protein levels of transgenic tau.
“Importantly, flamenco mutations do not affect total protein levels of transgenic tau (Supplementary Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
Protein levels of piwi are depleted in brains of tau transgenic Drosophila.
“In addition, protein levels of piwi, a central regulator of piRNA biogenesis, are depleted in brains of tau transgenic Drosophila based on both immunofluorescence (Fig. 3b) and western blotting (Fig. 3c).”
Quote in the paperSubstantial claim - Findingown data
Transposable element transcripts increased in response to pathogenic tau generally have a greater magnitude of change than those decreased.
“These analyses also revealed that the transposable elements transcripts that are increased in response to pathogenic tau generally have a greater magnitude of change than transposable element transcripts that are decreased in response to pathogenic tau.”
Quote in the paperNot a substantial claim - Findingown data
Compared to tau expressed alone, piwi overexpression significantly reduces transposable element transcripts that are elevated in tau transgenic Drosophila.
“Compared to tau expressed alone, piwi overexpression significantly reduces transposable element transcripts that are elevated in tau transgenic Drosophila (Fig. 3f).”
Quote in the paperSubstantial claim - Findingown data
A significant increase of transposable element mobilization is detected in tau transgenic Drosophila based on both GFP fluorescence and immunoblotting at day ten of adulthood.
“Accordingly, we do not detect transposable element mobilization in tauV337M transgenic Drosophila based on either gypsy-TRAP GFP reporter fluorescence or immunoblotting at day one of adulthood, but detect a significant increase of transposable element mobilization in tau transgenic Drosophila based on both GFP fluorescence and immunoblotting at day ten of adulthood.”
Quote in the paperSubstantial claim - Findingown data
Dietary restriction suppresses tau-induced neuronal death.
“TUNEL reveals that dietary restriction suppresses tau-induced neuronal death (Fig. 5c)”
Quote in the paperSubstantial claim - Findingown data
In cerebellum, 76 Alzheimer's disease and 78 progressive supranuclear palsy samples cluster together in the scatter plot.
“Similar to cortex, the 76 Alzheimer’s disease and 78 progressive supranuclear palsy samples cluster together in the scatter plot, and control samples do not generally belong to this cluster (Supplementary Fig. 4d, P<2*10−6).”
Quote in the paperNot a substantial claim - Findingown data
Combining the two P-values for non-LTR overrepresentation in cortex by Fisher's method gives P=2×10−8.
“We used the sumlog function from the metap package v0.8 to combine these two P-values by Fisher’s method (P=2×10−8).”
Quote in the paperNot a substantial claim - Findingown data
Non-LTR retrotransposons are overrepresented in the decreased transposable elements in cerebellum (adjusted P=0.01).
“Similarly, we confirmed that the non-LTR retrotransposon are also overrepresented in the decreased transposable elements in cerebellum (adjusted P=0.01).”
Quote in the paperNot a substantial claim - Findingown data
3TC treatment significantly reduces tau-induced neuronal death.
“3TC treatment significantly reduces tau-induced neuronal death (Fig. 6c)”
Quote in the paperSubstantial claim - Findingown data
A Kolmogorov-Smirnov test showed that control samples do not generally belong to the Alzheimer's disease/progressive supranuclear palsy cluster in cortex (P<3*10−7).
“A Kolmogorov–Smirnov Test showed that the control samples do not generally belong to this cluster (Fig. 7e, P<3*10−7).”
Quote in the paperNot a substantial claim - Findingown data
Tau transgenic flies treated with 10 mM 3TC have significantly reduced gypsy-TRAP reporter activation in the brain.
“Tau transgenic flies treated with 10 mM 3TC have significantly reduced gypsy-TRAP reporter activation in the brain (Fig. 6a, b)”
Quote in the paperSubstantial claim - Findingown data
66% dietary restriction reduces tau-induced transposable element mobilization in adult Drosophila neurons.
“we find that 66% dietary restriction reduces tau-induced transposable element mobilization in adult Drosophila neurons (Fig. 5a, b)”
Quote in the paperSubstantial claim - Findingown data
A scatterplot of the first two principal components showed that Alzheimer's disease and progressive supranuclear palsy samples cluster together in cortex.
“A scatterplot of the first two principal components showed that Alzheimer’s disease and progressive supranuclear palsy samples cluster together (Fig. 7d).”
Quote in the paperNot a substantial claim - Findingown data
Both mechanisms of transposable element suppression are compromised in tauopathy.
“We find that both mechanisms of transposable element suppression are compromised in tauopathy”
Quote in the paperSubstantial claim - Findingown data
Differentially expressed transposable elements are identified in Alzheimer's disease and progressive supranuclear palsy postmortem human brains.
“We apply an unbiased transcriptomic approach to extend our findings to postmortem human brains and identify differentially expressed transposable elements in Alzheimer’s disease and progressive supranuclear palsy”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
- Findingown data
The observed number of non-LTR retrotransposons among downregulated transposable elements in Alzheimer's disease cortex is significantly more than expected, since only 239 (22%) of the total 1073 human transposable elements are non-LTR (hypergeometric test, P=0.002).
“This is significantly more than expected, since only 239 (22%) of the total 1073 human transposable elements are non-LTR (hypergeometric test, P=0.002).”
Quote in the paperSubstantial claim - Findingown data
Endogenous retroviruses are overrepresented in the upregulated transposable elements in cerebellum (adjusted P=0.0003).
“We used similar tests to show that endogenous retroviruses are overrepresented in the upregulated transposable elements in cortex (adjusted P=0.004) and cerebellum (adjusted P=0.0003).”
Quote in the paperNot a substantial claim - Findingown data
In cerebellum, control samples do not generally belong to the Alzheimer's disease/progressive supranuclear palsy cluster (P<2*10−6).
“Similar to cortex, the 76 Alzheimer’s disease and 78 progressive supranuclear palsy samples cluster together in the scatter plot, and control samples do not generally belong to this cluster (Supplementary Fig. 4d, P<2*10−6).”
Quote in the paperNot a substantial claim - Findingown data
Among transposable elements downregulated in cortex and cerebellum of both tauopathies, non-LTR retrotransposons are significantly over-represented.
“while non-LTR retrotransposons are significantly over-represented among transposable elements that are downregulated in cortex and cerebellum of both tauopathies (Fig. 7c, Supplementary Fig. 8c)”
Quote in the paperNot a substantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
- Findingown data
All four transposable elements downregulated in Alzheimer's disease cortex are non-LTR retrotransposons.
“All of the four transposable elements that are downregulated in Alzheimer’s disease cortex are non-LTR retrotransposons.”
Quote in the paperNot a substantial claim - Findingown data
Endogenous retroviruses are overrepresented in the upregulated transposable elements in cortex (adjusted P=0.004).
“We used similar tests to show that endogenous retroviruses are overrepresented in the upregulated transposable elements in cortex (adjusted P=0.004) and cerebellum (adjusted P=0.0003).”
Quote in the paperNot a substantial claim - Findingown data
The distance of control samples to the median center of the first two principal components is significantly further compared to tauopathy samples in both cortex and cerebellum.
“the distance of control samples to the median center is significantly further compared to tauopathy samples in both cortex (Fig. 7e) and cerebellum (Supplementary Fig. 8e)”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
- Findingown data
3TC treatment significantly alleviates tau-induced locomotor deficits in a dose-dependent manner.
“significantly alleviates tau-induced locomotor deficits (Fig. 6d) in a dose-dependent manner (Supplementary Fig. 7a, b)”
Quote in the paperSubstantial claim - Findingown data
DESeq2 and a likelihood ratio test identified 19 transposable elements with variable expression in cortex across Alzheimer's disease, progressive supranuclear palsy, and control conditions.
“We used DESeq2 package and a likelihood ratio test to identify 19 transposable elements that have variable expression in any of the three Alzheimer’s disease, progressive supranuclear palsy, or control conditions in cortex (Supplementary Table 7).”
Quote in the paperSubstantial claim - Findingown data
Non-LTR retrotransposons are overrepresented among downregulated transposable elements in progressive supranuclear palsy cortex (P=5×10−7).
“Similarly, the non-LTR retrotransposon are overrepresented among downregulated transposable elements in progressive supranuclear palsy cortex (P=5×10−7).”
Quote in the paperNot a substantial claim - Findingown data
Control samples have significantly lower values in the second principal component compared to Alzheimer's disease and progressive supranuclear palsy in both cortex and cerebellum.
“control samples have significantly lower values in the second principal component compared to Alzheimer’s disease and progressive supranuclear palsy in both cortex (Fig. 7d) and cerebellum (Supplementary Fig. 8d)”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
- Findingown data
Among transposable elements upregulated in cortex and cerebellum of both tauopathies, endogenous retroviruses are significantly over-represented.
“Among transposable elements that are upregulated in cortex and cerebellum of both tauopathies, we found a significant over-representation of endogenous retroviruses”
- Also stated in: § DISCUSSION · plain
“Among upregulated transposable elements in human tauopathy, the human endogenous retrovirus (HERV) family, including HERV-K, is significantly over-represented”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
- Also stated in: § DISCUSSION · plain
- Findingown data
Many members of the copia family are increased at the transcript level based on both RNA-seq and NanoString analyses.
“Since many members of the copia family are increased at the transcript level based on both RNA-seq and NanoString analyses”
Quote in the paperSubstantial claim - Findingown data
Dietary restriction significantly reduces the copia family and several other transposable elements that are increased in tau transgenic Drosophila at the transcript level.
“dietary restriction significantly reduces the copia family at the transcript level, as well as several other transposable elements that are significantly increased in tau transgenic Drosophila (Supplementary Fig. 6)”
Quote in the paperSubstantial claim - Interpretationown data
Suppression of transposable element mobilization and resulting neurodegeneration can be achieved by environmental and pharmacological intervention.
“In addition, we show that that suppression of transposable element mobilization and resulting neurodegeneration can be achieved by environmental and pharmacological intervention.”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin decondensation and depletion of piwi/piRNAs are major mechanistic links between pathogenic tau and loss of transposable element control.
“We identify heterochromatin decondensation and depletion of piwi/piRNAs as major mechanistic links between pathogenic tau and loss of transposable element control”
- Also stated in: § Abstract · plain
“Mechanistically, we find that heterochromatin decondensation and reduction of piwi/piRNAs drive transposable element dysregulation in tauopathy.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Interpretationown data
Loss of transposable element silencing in tau transgenic Drosophila is causally linked to neuronal death.
“Taken together, these data suggest that loss of transposable element silencing in tau transgenic Drosophila is causally linked to neuronal death and promotes neuronal death through aberrant activation of the cell cycle in post-mitotic neurons.”
Quote in the paperSubstantial claim - Interpretationown data
Aberrant expression of transposable elements in tauopathy is a regulated, rather than stochastic, process.
“These data suggest that aberrant expression of transposable elements in tauopathy is a regulated, rather than stochastic, process.”
Quote in the paperSubstantial claim - Interpretationown data
Loss of transposable element silencing promotes neuronal death through aberrant activation of the cell cycle in post-mitotic neurons.
“Taken together, these data suggest that loss of transposable element silencing in tau transgenic Drosophila is causally linked to neuronal death and promotes neuronal death through aberrant activation of the cell cycle in post-mitotic neurons.”
Quote in the paperSubstantial claim - Interpretationown data
Tau-induced reduction of piwi and piRNAs is a major contributor to the transposable element expression profile in brains of tau transgenic Drosophila.
“These data indicate that pan-neuronal piwi knockdown (Supplementary Fig. 4a) is sufficient to elevate transcript levels of most of the transposable elements that are increased in tauR406W transgenic Drosophila (Fig. 3d), suggesting that tau-induced reduction of piwi and piRNAs is a major contributor to the transposable element expression profile in brains of tau transgenic Drosophila.”
Quote in the paperSubstantial claim - Interpretationown data
Tau-induced heterochromatin decondensation contributes to transposable element dysregulation in brains of tau transgenic Drosophila.
“In the context of our previous report identifying tau-induced heterochromatin decondensation as a central mediator of neurotoxicity in tauopathy, these data suggest that tau-induced heterochromatin decondensation contributes to transposable element dysregulation in brains of tau transgenic Drosophila.”
Quote in the paperSubstantial claim - Interpretationown data
Transposable element dysregulation is conserved in human tauopathy.
“suggesting that transposable element dysregulation is conserved in human tauopathy.”
Quote in the paperSubstantial claim - Interpretationown data
Aberrant transposable element expression is relevant to the greater family of sporadic tauopathies that involve only wild-type tau.
“suggesting that aberrant transposable element expression is relevant to the greater family of sporadic tauopathies that involve only wild-type tau.”
Quote in the paperSubstantial claim - Interpretationown data
Transposable element dysregulation is a key mediator of neuronal death in tauopathies.
“Here we identify transposable element dysregulation as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologically characterized by deposits of tau protein in the brain.”
Quote in the paperSubstantial claim - Interpretationown data
Transposable element dysregulation in human tauopathy is a regulated rather than stochastic process.
“these data suggest that transposable element dysregulation in human tauopathy is a regulated rather than stochastic process”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
- Interpretationown data
Pathogenic tau drives neuronal death through a novel, therapeutically targetable mechanism.
“We have uncovered a novel, therapeutically targetable mechanism whereby pathogenic tau drives neuronal death”
Quote in the paperSubstantial claim - Interpretationown data
Transposable element dysregulation is causal for the disease process in tauopathy.
“Taken together, these data provide additional evidence that transposable element dysregulation is causal for the disease process in tauopathy”
Quote in the paperSubstantial claim - Interpretationown data
Our studies reveal a previously undocumented role for heterochromatin- and piRNA-mediated transposable element silencing in the brain.
“our studies reveal a previously undocumented role for heterochromatin- and piRNA-mediated transposable element silencing in the brain”
Quote in the paperSubstantial claim - Interpretationreasoning
Tau-induced transposable element dysregulation is deleterious to neuronal survival.
“suggest that tau-induced transposable element dysregulation is deleterious to neuronal survival”
Quote in the paperSubstantial claim - Interpretationown data
Dysregulation of transposable elements is a consequence of pathogenic tau.
“our studies identify dysregulation of transposable elements as a consequence of pathogenic tau”
Quote in the paperSubstantial claim - Interpretationown data
Transposable element dysregulation is responsive to environmental and pharmacological inhibition.
“and is responsive to environmental and pharmacological inhibition”
Quote in the paperSubstantial claim - Interpretationown data
Dysregulation of transposable elements is a driver of aberrant cell cycle activation in neurons and subsequent neuronal death.
“and a driver of aberrant cell cycle activation in neurons and subsequent neuronal death”
Quote in the paperSubstantial claim - Interpretationreasoning
Reverse transcriptase inhibitors have significant potential as a novel therapeutic strategy for the treatment of neurodegenerative tauopathies, including Alzheimer's disease.
“Based on the data presented in the current study, reverse transcriptase inhibitors have significant potential as a novel therapeutic strategy for the treatment of neurodegenerative tauopathies, including Alzheimer’s disease”
Quote in the paperSubstantial claim- Rests on an assumption: The protective effects of 3TC are mediated by inhibition of reverse transcriptase.
- Classified as probably not a substantial claim. 34
- May combine two claims. 23
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenThe extent to which transposable elements are involved in human disorders and drive disease pathogenesis is currently unknown.
“While transposable element activation has also been implicated in cancer6, and TDP-43 mediated neurodegeneration7–9, the extent to which transposable elements are involved in human disorders and drive disease pathogenesis is currently unknown.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [6] Burns, K. H. Transposable elements in cancer. Nat. Rev. Cancer 17, 415–424 (2017). source
- cites [7] Li, W., Jin, Y., Prazak, L., Hammell, M. & Dubnau, J. Transposable elements in TDP-43-mediated neurodegenerative disorders. PLoS One 7, e44099 (2012). source
- cites [8] Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl. Med. 7, 307ra153 (2015). source
- cites [9] Krug, L. et al. Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 13, e1006635 (2017). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDrosophila models of human tauopathy have progressive, age-associated neuronal death, a shortened lifespan, and decreased locomotor activity.
“Drosophila models of human tauopathy have progressive, age-associated neuronal death, a shortened lifespan, and decreased locomotor activity10,11.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
The Results section ('Tau transgenic Drosophila have widespread alterations in chromatin structure'; page unavailable) says that human tau expression causes progressive neurodegeneration. The Results section ('Genetic manipulation of chromatin structure modifies tau neurotoxicity'; page unavailable) reports significantly decreased locomotor activity at ten days of age. Our copy does not establish a shortened lifespan or explicitly describe the neuronal death as age-associated. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [11] Wittmann, C. W. et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711–714 (2001). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationpiRNAs are known to exist in the Drosophila and mammalian brain.
“While the function of piwi in regard to piRNA production and transposable element silencing is well established in the germline29, and piRNAs are known to exist in the Drosophila and mammalian brain30,31, it is currently unknown if piwi reduction affects transposable element transcripts in the brain.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [30] Ghildiyal, M. et al. Endogenous siRNAs derived from transposons and mRNAs in Drosophila somatic cells. Science 320, 1077–1081 (2008). source
The passage describing Fig. 4C (indexed as Abstract; page unavailable) reports piRNA-like RNAs in Drosophila ago2-mutant heads. It does not establish that these are piRNAs in the brain, and the paper provides no evidence for piRNAs in mammalian brains. Its findings therefore support only a narrower part of the claim. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [31] Lee, E. J. et al. Identification of piRNAs in the central nervous system. RNA 17, 1090–1099 (2011). source
May combine two claims.
PremisecitationLoss-of-function mutations in Su(var)205 or Su(var)3-9 further deplete constitutive heterochromatin in tau transgenic Drosophila and enhance tau-induced neuronal death.
“Tau-induced heterochromatin relaxation plays a causal role in mediating neurodegeneration, as loss of function mutations in Su(var)20533 and Su(var)3-934, genes encoding heterochromatin protein 1 (HP1) and a histone 3, lysine 9 methyltransferase, respectively, further deplete constitutive heterochromatin in tau transgenic Drosophila and enhance tau-induced neuronal death10.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEctopic expression of proteins associated with aberrant activation of the cell cycle in post-mitotic neurons is a well-described feature of human tauopathy.
“Ectopic expression of proteins associated with aberrant activation of the cell cycle in post-mitotic neurons is a well-described feature of human tauopathy25.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Frost, B., Götz, J. & Feany, M. B. Connecting the dots between tau dysfunction and neurodegeneration. Trends Cell Biol. 25, 46–53 (2015). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationpiRNAs have recently been reported to be differentially expressed in the human Alzheimer's disease brain.
“Since flamenco is known to encode a major piRNA cluster3,26, and piRNAs have recently been reported to be differentially expressed in the human Alzheimer’s disease brain27,28, we next determined if piRNAs are involved in dysfunctional transposable element control in the tauopathy brain.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [27] Roy, J., Sarkar, A., Parida, S., Ghosh, Z. & Mallick, B. Small RNA sequencing revealed dysregulated piRNAs in Alzheimer’s disease and their probable role in pathogenesis. Mol. Biosyst. 13, 565–576 (2017). source
- cites [28] Qiu, W. et al. Transcriptome-wide piRNA profiling in human brains of Alzheimer’s disease. Neurobiol. Aging 57, 170–177 (2017). source
May combine two claims.
PremisecitationHomozygous permissive loss-of-function alleles of flamenco allow transposable element mobilization and increase transposable element copy number within the Drosophila genome.
“Homozygous “permissive” loss of function alleles of flamenco allow transposable element mobilization and increase transposable element copy number within the Drosophila genome23,24.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [23] Pélisson, A. et al. About the origin of retroviruses and the co-evolution of the gypsy retrovirus with the Drosophila flamenco host gene. Genetica 100, 29–37 (1997). source
- cites [24] Mével-Ninio, M., Pelisson, A., Kinder, J., Campos, A. R. & Bucheton, A. The flamenco locus controls the gypsy and ZAM retroviruses and is required for Drosophila oogenesis. Genetics 175, 1615–1624 (2007). source
The paper states that homozygous permissive flamenco strains allow high levels of gypsy replicative transposition, and its Discussion reports that flamenco mutations remove repression of gypsy and ZAM. But the passage on gypsy copy number also says most permissive stocks remain stable because they lack functional gypsy proviruses. It therefore does not support an unqualified increase in transposable-element copy number. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationNeuronal phenotypes of tau transgenic Drosophila mimic features of human Alzheimer's disease and associated tauopathies.
“In addition, neuronal phenotypes of tau transgenic Drosophila mimic features of human Alzheimer’s disease and associated tauopathies, including but not limited to aberrant tau phosphorylation13, oxidative stress14, DNA damage15,16, decondensation of constitutive heterochromatin10, synaptic dysfunction17 and activation of the cell cycle in post-mitotic neurons18.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
- cites [13] Steinhilb, M. L., Dias-Santagata, D., Fulga, T. A., Felch, D. L. & Feany, M. B. Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol. Biol. Cell 18, 5060–5068 (2007). source
- cites [14] Dias-Santagata, D., Fulga, T. A., Duttaroy, A. & Feany, M. B. Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J. Clin. Invest. 117, 236–245 (2007). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe flamenco locus harbors piRNAs that specifically degrade gypsy, Idefix, and ZAM transposable element transcripts, among others.
“The flamenco locus harbors piRNAs that specifically degrade gypsy, Idefix, and ZAM transposable element transcripts24, among others.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Mével-Ninio, M., Pelisson, A., Kinder, J., Campos, A. R. & Bucheton, A. The flamenco locus controls the gypsy and ZAM retroviruses and is required for Drosophila oogenesis. Genetics 175, 1615–1624 (2007). source
The Results passage on P-element-induced mutations reports that flamenco is likely required for the accumulation of gypsy rasiRNAs, and the Discussion reports repression of gypsy and ZAM. Our copy does not establish that flamenco harbors piRNAs that directly degrade those transcripts, and the searched passages provide no support for Idefix. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation3TC is reported to reduce age-associated transposable element mobilization in the Drosophila fat body.
“Like dietary restriction, 3TC is reported to reduce age-associated transposable element mobilization in the Drosophila fat body5”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl. Acad. Sci. USA 113, 11277–11282 (2016). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation3TC is FDA-approved for treatment of HIV/AIDS and Hepatitis B, both of which are caused by retroviruses.
“that is FDA-approved for treatment of HIV/AIDS and Hepatitis B, both of which are caused by retroviruses”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Coates, J. A. et al. (–)-2′-Deoxy-3′-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob. Agents Chemother. 36, 733–739 (1992). source
The Discussion reports that 3TC inhibits HIV-1 and HIV-2 replication in vitro and calls it a candidate for AIDS treatment, with clinical trials in progress. It does not support the claim that 3TC was FDA-approved or used to treat hepatitis B, nor does it classify hepatitis B as a retroviral disease. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation3TC (Lamivudine) is a water-soluble nucleoside analog inhibitor of reverse transcriptase.
“3TC (Lamivudine) is a water-soluble nucleoside analog inhibitor of reverse transcriptase38”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Coates, J. A. et al. (–)-2′-Deoxy-3′-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob. Agents Chemother. 36, 733–739 (1992). source
The introduction identifies 3TC as a nucleoside analog, and the Discussion says its triphosphate form is assumed to inhibit viral reverse transcriptase; the paper presents its data as consistent with that mechanism. Our copy does not state that 3TC is water-soluble, and it does not directly establish reverse-transcriptase inhibition. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationElevated HERV-K transcripts are associated with amyotrophic lateral sclerosis and many human cancers.
“Elevated HERV-K transcripts are associated with amyotrophic lateral sclerosis (ALS)8 and many human cancers, including melanoma, breast cancer, germ cell tumors, renal cancer, and ovarian cancer42”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [8] Li, W. et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci. Transl. Med. 7, 307ra153 (2015). source
- cites [42] Gonzalez-Cao, M. et al. Human endogenous retroviruses and cancer. Cancer Biol. Med. 13, 483–488 (2016). source
Citation 42 is attached to the cancer examples, while ALS has a separate citation. In “Expression of HERVs in cancer cells” (page unavailable), the paper reports elevated HERV-K-containing mRNA in breast cancer patients and HERV-K protein in several cancers, but it does not establish elevated HERV-K transcripts across all the listed cancers; the renal-cancer transcripts it identifies are HERV-E. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDietary restriction reduces age-related transposable element mobilization events in the Drosophila fat body.
“reduces age-related transposable element mobilization events in the Drosophila fat body5”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl. Acad. Sci. USA 113, 11277–11282 (2016). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitation9 cortex and 15 cerebellum samples were excluded because they had an RNA Integrity Number (RIN) less than 7.
“In this study, we also excluded 9 cortex and 15 cerebellum samples that had an RNA Integrity Number (RIN)63 less than 7.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [63] Schroeder, A. et al. The RIN: an RNA integrity number for assigning integrity values to RNA measurements. BMC Mol. Biol. 7, 3 (2006). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationSample sizes are similar to or greater than those reported in previous publications.
“Sample sizes are similar to or greater than those reported in previous publications4,5,10.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [4] Li, W. et al. Activation of transposable elements during aging and neuronal decline in D rosophila. Nat. Neurosci. 16, 529–531 (2013). source
- cites [5] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl. Acad. Sci. USA 113, 11277–11282 (2016). source
The SI Materials and Methods, “Life Span Assays” (page unavailable), reports at least 250 flies per condition; “RNA-seq” (page unavailable) reports at least three biological replicates per condition. These establish sample sizes for this previous publication, but our copy cannot establish whether the citing study’s sample sizes are similar or greater. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [10] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDietary restriction extends lifespan in invertebrate and vertebrate systems.
“Dietary restriction extends lifespan in invertebrate and vertebrate systems36”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [36] Longo, V. D. et al. Interventions to slow aging in humans: are we ready? Aging Cell 14, 497–510 (2015). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationCells have two layers of defense against potentially deleterious transposable element activation: transcription is limited by heterochromatin-mediated silencing, and transcripts are cleared by piRNA-mediated degradation.
“Based on current understanding, cells have two layers of defense against potentially deleterious transposable element activation: 1) Transposable element transcription is limited by heterochromatin-mediated silencing, and 2) Transposable element transcripts are cleared from the cell by piRNA-mediated degradation”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [3] Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in D rosophila. Cell 128, 1089–1103 (2007). source
- cites [39] Andersen, P. R., Tirian, L., Vunjak, M. & Brennecke, J. A heterochromatin-dependent transcription machinery drives piRNA expression. Nature 549, 54–59 (2017). source
The Abstract and Discussion (pages unavailable) support heterochromatin-mediated repression of transposon transcription. The Abstract also says the piRNA pathway targets transposons post-transcriptionally, but our copy does not specify that this clears their transcripts through degradation. (LLM, conf=0.83)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataDietary restriction and 3TC suppress tau-induced transposable element dysregulation and tau-induced neurotoxicity.
“Dietary restriction and 3TC (lamivudine), a nucleoside analog inhibitor of reverse transcriptase that is FDA-approved for the treatment of HIV and Hepatitis B, suppress tau-induced transposable element dysregulation and tau-induced neurotoxicity.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn tauR406W transgenic Drosophila, multiple members of some transposable element subgroups (e.g., copia, HeT-A, Quasimodo) are increased, while members of other subgroups (e.g., Burdock, Blood) are decreased.
“For several subgroups of transposable elements, we found that multiple members of the same subgroup, such as copia, HeT-A, and Quasimodo, are increased in tauR406W transgenic Drosophila, while members of other subgroups, such as Burdock and Blood, are decreased in tauR406W transgenic Drosophila.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRNA-seq of tauR406W transgenic Drosophila heads at day 10 identified 50 transposable elements significantly increased and 60 significantly decreased at the transcript level compared to controls.
“We identified 50 transposable elements that are significantly increased at the transcript level in tau transgenic Drosophila compared to controls, and 60 transposable elements that are significantly decreased”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTwo different heterozygous loss-of-function alleles of flamenco do not induce neuronal death or locomotor deficits in controls.
“Two different heterozygous loss of function alleles of flamenco23,24 do not induce neuronal death or locomotor deficits in controls, but significantly enhance neuronal death in tauR406W transgenic Drosophila (Fig. 2a) and exacerbate tau-induced locomotor deficits (Fig. 2b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNanoString confirmed 14 of 25 probes as significantly increased and 6 of 22 probes as significantly decreased in heads of tauR406W transgenic Drosophila.
“14 of 25 probes were confirmed by NanoString as significantly increased (Fig. 1c), while 6 of 22 probes were confirmed as significantly decreased in heads of tauR406W transgenic Drosophila (Fig. 1d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPan-neuronal expression of tauWT significantly increases 10 of 25 and decreases 8 of 22 probes recognizing transposable elements identified as increased or decreased, respectively, in tauR406W Drosophila.
“Pan-neuronal expression of tauWT significantly increases 10 of 25, and decreases 8 of 22 probes recognizing transposable elements that were identified as increased or decreased, respectively, in tauR406W Drosophila based on RNA-seq (Supplementary Fig. 2b, c)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSpecific subgroups of transposable elements are upregulated in human tauopathy, while other subgroups are downregulated.
“we found that specific subgroups of transposable elements are upregulated in human tauopathy, while other subgroups are downregulated”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataA similar analysis on cerebellum showed that 20 transposable elements have variable expression in Alzheimer's disease, progressive supranuclear palsy, or control.
“We performed a similar analysis on cerebellum, which showed that 20 transposable elements have variable expression in Alzheimer’s disease, progressive supranuclear palsy, or control (Supplementary Fig. 4a, b, c, Supplementary Table 7).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataIn cerebellum, the majority of control samples are below the orange diagonal line.
“In particular, the majority of control samples are below the orange diagonal line.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataNanoString data show a similar expression trend of most transposable elements identified as differentially expressed in tau transgenic Drosophila by RNA-seq, but some elements are not confirmed as differentially expressed by NanoString.
“While NanoString data show a similar expression trend of most of the transposable elements that are identified as differentially expressed in tau transgenic Drosophila by RNA-seq, some of the elements are not confirmed as differentially expressed by NanoString”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataGenetic, dietary and pharmacological approaches reduce transposable element dysregulation and suppress tau-induced neurotoxicity in Drosophila.
“We identify genetic, dietary and pharmacological approaches to reduce transposable element dysregulation and suppress tau-induced neurotoxicity in Drosophila”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAnalyses of human transposable elements reveal a significant transcriptional increase in endogenous retroviruses and a significant decrease in non-LTR retroelements in postmortem human brain of both Alzheimer's disease and progressive supranuclear palsy patients.
“Taken together, analyses of human transposable elements clearly reveal a significant transcriptional increase in endogenous retroviruses, and a significant decrease in non-LTR retroelements in postmortem human brain of both Alzheimer’s disease and progressive supranuclear palsy patients”
Quote in the paperSubstantial claim- Rests on an assumption: The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
- Rests on an assumption: Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
May combine two claims.
Interpretationown dataHeterochromatin decondensation and depletion of piwi and piRNAs are key mechanisms driving transposable element dysregulation and subsequent neuronal death in tau-mediated neurodegeneration.
“Taken together, our studies identify heterochromatin decondensation and depletion of piwi and piRNAs as key mechanisms driving transposable element dysregulation and subsequent neuronal death in tau-mediated neurodegeneration.”
- Also stated in: § Abstract · boosted
“Taken together, our data identify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element dysregulation as a novel, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · boosted
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMany transposable elements are embedded within highly condensed constitutive heterochromatin and are epigenetically silenced.
“Many transposable elements are embedded within highly condensed constitutive heterochromatin, and are thus epigenetically silenced2.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Slotkin, R. K. & Martienssen, R. Transposable elements and the epigenetic regulation of the genome. Nat. Rev. Genet. 8, 272–285 (2007). source
Classified as probably not a substantial claim.
PremisecitationTransposable element transcripts are targets of a conserved piRNA pathway that binds to them and mediates their degradation.
“In addition, transposable element transcripts are the targets of a well-conserved pathway involving piRNAs, small regulatory RNAs that bind to transposable element transcripts and mediate their degradation3.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in D rosophila. Cell 128, 1089–1103 (2007). source
Classified as probably not a substantial claim.
PremisecitationConstitutive heterochromatin is a silencing mechanism for transposable elements.
“Based on previous studies that identified constitutive heterochromatin as a silencing mechanism for transposable elements35, we next determined if genetically promoting heterochromatin relaxation affects the transposable elements that are differentially expressed in tau transgenic Drosophila.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Fedoroff, N. V. Presidential address. Transposable elements, epigenetics, and genome evolution. Science 338, 758–767 (2012). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe complexity and repetitive nature of transposable elements presents challenges to RNA-seq analysis, which has a greater frequency of false positives and negatives than analysis of canonical messenger RNAs.
“The complexity and repetitive nature of transposable elements presents challenges to RNA-seq analysis, which is associated with a greater frequency of false positives and negatives compared to analysis of canonical messenger RNAs.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataHeterochromatin decondensation, piwi/piRNA depletion and consequent transposable element dysregulation are a novel, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.
“Taken together, our data identify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element dysregulation as a novel, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataPathogenic tau acts through piwi reduction to mediate aberrant cell cycle activation and consequent neuronal death.
“Based on PCNA staining, pan-neuronal piwi reduction is also sufficient to activate the cell cycle in neurons (Supplementary Fig. 4b), suggesting that pathogenic tau acts through piwi reduction to mediate aberrant cell cycle activation and consequent neuronal death.”
Quote in the paperSubstantial claim- Rests on an assumption: piwi is a central regulator of piRNA biogenesis.
May combine two claims.
Interpretationown dataTau-induced piwi reduction depletes piRNAs, which significantly increases transposable element transcripts and causally contributes to tau-induced neurotoxicity.
“These data suggest that tau-induced piwi reduction depletes piRNAs, which significantly increases transposable element transcripts and causally contributes to tau-induced neurotoxicity.”
Quote in the paperSubstantial claim- Rests on an assumption: piwi is a central regulator of piRNA biogenesis.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFlamenco is known to encode a major piRNA cluster.
“Since flamenco is known to encode a major piRNA cluster3,26, and piRNAs have recently been reported to be differentially expressed in the human Alzheimer’s disease brain27,28, we next determined if piRNAs are involved in dysfunctional transposable element control in the tauopathy brain.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3] Brennecke, J. et al. Discrete small RNA-generating loci as master regulators of transposon activity in D rosophila. Cell 128, 1089–1103 (2007). source
- cites [26] Sarot, E., Payen-Groschêne, G., Bucheton, A. & Pélisson, A. Evidence for a piwi-dependent RNA silencing of the gypsy endogenous retrovirus by the Drosophila melanogaster flamenco gene. Genetics 166, 1313–1321 (2004). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe function of piwi in regard to piRNA production and transposable element silencing is well established in the germline.
“While the function of piwi in regard to piRNA production and transposable element silencing is well established in the germline29, and piRNAs are known to exist in the Drosophila and mammalian brain30,31, it is currently unknown if piwi reduction affects transposable element transcripts in the brain.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Siomi, M. C., Sato, K., Pezic, D. & Aravin, A. A. PIWI-interacting small RNAs: the vanguard of genome defence. Nat. Rev. Mol. Cell Biol. 12, 246–258 (2011). source
May combine two claims.
Interpretationown dataEnhancement of tau-induced neurotoxicity by flamenco loss of function is due to activation of specific elements affected by pathogenic tau, and/or additional elements outside of the NanoString codeset.
“Rather than a general effect on the panel of transposable elements that are dysregulated by pathogenic tau, these analyses suggest that enhancement of tau-induced neurotoxicity by flamenco loss of function is due to activation of specific elements affected by pathogenic tau, and/or additional elements outside of our NanoString codeset.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitation12 cortex and 10 cerebellum samples were excluded due to low quality.
“12 cortex (syn6126114) and 10 cerebellum (syn6126119) samples were excluded due to low quality61,62.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [61] Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). source
- cites [62] Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEqual loading was assessed by Ponceau S staining.
“Equal loading was assessed by Ponceau S staining.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductreasoningAfter filtering, 80 Alzheimer's disease, 82 progressive supranuclear palsy, and 21 control cortex samples were available.
“After this filtering, 80 Alzheimer’s disease, 82 progressive supranuclear palsy, and 21 control cortex samples were available, as well as 76 Alzheimer’s disease, 78 progressive supranuclear palsy, and 25 control cerebellum samples.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningExperiments utilizing the gypsy-TRAP reporter or flamenco require two genetic elements on the X chromosome, thus all data points are from female flies.
“Experiments utilizing the gypsy-TRAP reporter or flamenco require two genetic elements on the X chromosome, thus all data points are from female flies.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationRetrotransposons encode machinery, including a capsid protein, polymerase, integrase, and reverse transcriptase, needed to copy themselves and insert the new copy into the genome.
“Like retroviruses, retrotransposons encode machinery, including a capsid protein, polymerase, integrase, and reverse transcriptase, needed to copy themselves and insert the new copy into the genome37”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [37] Sultana, T., Zamborlini, A., Cristofari, G. & Lesage, P. Integration site selection by retroviruses and transposable elements in eukaryotes. Nat. Rev. Genet. 18, 292–308 (2017). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningAfter filtering, 76 Alzheimer's disease, 78 progressive supranuclear palsy, and 25 control cerebellum samples were available.
“After this filtering, 80 Alzheimer’s disease, 82 progressive supranuclear palsy, and 21 control cortex samples were available, as well as 76 Alzheimer’s disease, 78 progressive supranuclear palsy, and 25 control cerebellum samples.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningAn equal number of males and females were used in all Drosophila assays with the exception of gypsy-TRAP and flamenco genetic manipulations.
“An equal number of males and females were used in all Drosophila assays with the exception of gypsy-TRAP and flamenco genetic manipulations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe quality of bases in the cleaned reads was above 28 (Sanger/Illumina 1.9 encoding).
“The quality of bases in the cleaned reads was above 28 (Sanger/Illumina 1.9 encoding).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenSamples were randomized in all Drosophila studies.
“Samples were randomized in all Drosophila studies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenInvestigators were blinded to genotype in all immunohistochemistry, immunofluorescence, and locomotor activity assays.
“Investigators were blinded to genotype in all immunohistochemistry, immunofluorescence, and locomotor activity assays.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
It is currently unknown whether piwi reduction affects transposable element transcripts in the brain.
“it is currently unknown if piwi reduction affects transposable element transcripts in the brain.”
The paper relies on this without support.
Neuronal death in Drosophila models of tauopathy is age-dependent.
“Neuronal death in Drosophila models of tauopathy is age-dependent.”
The paper relies on this without support.
piwi is a central regulator of piRNA biogenesis.
“In addition, protein levels of piwi, a central regulator of piRNA biogenesis, are depleted in brains of tau transgenic Drosophila based on both immunofluorescence (Fig. 3b) and western blotting (Fig. 3c).”
The paper relies on this without support.
The protective effects of 3TC are mediated by inhibition of reverse transcriptase.
“Tau transgenic flies treated with 10 mM 3TC have significantly reduced gypsy-TRAP reporter activation in the brain (Fig. 6a, b)”
The paper relies on this without support.
The human postmortem RNA-seq data accurately reflect antemortem transposable element expression.
“We next analyzed transposable element expression in human tauopathy using RNA-seq data from cortex (Fig. 7a, b) and cerebellum (Supplementary Fig. 8a, b) of postmortem human control, Alzheimer’s disease, and progressive supranuclear palsy patients”
The paper relies on this without support.
Differences in transposable element expression between tauopathy and control are not due to differences in cell-type composition.
“we found that specific subgroups of transposable elements are upregulated in human tauopathy, while other subgroups are downregulated”
The authors state this as an assumption.
Data distribution was assumed to be normal but this was not formally tested.
“Data distribution was assumed to be normal but this was not formally tested.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Expression of a disease-associated human Tau protein in Drosophila neurons elicited loss of H3K9me2, widespread retrotransposon activation, DNA damage, and neuronal cell death that could be rescued with NRTIs.
“Expression of a disease-associated human Tau protein in Drosophila neurons elicited loss of H3K9me2, widespread retrotransposon activation, DNA damage, and neuronal cell death that could be rescued with NRTIs139.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [139]
The Results sections report altered retrotransposon expression and mobilization, neuronal death, and reduced neuronal death after treatment with 3TC, a nucleoside reverse-transcriptase inhibitor. The Drosophila-model section also lists DNA damage among the model’s phenotypes. Our copy discusses tau-induced heterochromatin relaxation but does not establish the claimed loss of H3K9me2; it reports a rescue experiment with one inhibitor, 3TC, rather than NRTIs generally. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPostmortem AD brain samples exhibited increased markers of open chromatin and elevated expression of retrotransposons.
“Postmortem AD brain samples exhibited increased markers of open chromatin137 and elevated expression of retrotransposons138, 139.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [139]
The Results section (‘Aberrant transposable element transcription in human tauopathy’; page unavailable) reports increased expression of endogenous retroviruses in postmortem Alzheimer’s disease brain, but decreased expression of non-LTR retrotransposons. Thus, this source supports elevated expression of a subgroup, not an unqualified increase in retrotransposons. The open-chromatin clause carries a different citation (137) and is not attributed to this source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredDepletion of piwi proteins was shown to increase transposable element (TE) transcription in a Drosophila model of tauopathy.
“Depletion of piwi proteins was shown to increase transposable element (TE) transcription in a Drosophila model of tauopathy (77).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [77]
The Results section, “Piwi/piRNA depletion is a mechanistic driver of transposable element transcription in tauopathy,” reports that neuronal piwi knockdown elevated TE transcript levels in Drosophila. However, that knockdown experiment was performed without transgenic tau, so it does not directly show the effect of induced piwi depletion within tau-expressing flies. (LLM, conf=0.82)
Experimental — accuracy not yet measuredSuppression of RTE reduces tau activation and tau-induced neurotoxicity in tau transgenic Drosophila.
“suppression of RTE was shown to reduce tau activation and tau-induced neurotoxicity in tau transgenic Drosophila (77).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [77]
The Results section on dietary restriction and reverse-transcriptase inhibition reports that reducing transposable-element mobilization in tau-transgenic Drosophila also reduced tau-induced neuronal death. It does not report that these interventions reduced tau activation; the reduced reporter activation described there measures transposable-element mobilization, not tau activation. (LLM, conf=0.88)
Experimental — accuracy not yet measuredLeveraging RNA-seq data from AMP-AD, the Frost group discovered that retrotransposons, particularly of the HERV class, are elevated in brains of patients with AD and progressive supranuclear palsy (PSP), a primary tauopathy, compared to controls.
“Leveraging RNA-seq data from the Accelerating Medicines Partnership–Alzheimer's Disease (AMP-AD) project, the Frost group (Sun et al. 2018) discovered that retrotransposons, particularly of the HERV class, are elevated in brains of patients with AD and progressive supranuclear palsy (PSP), a primary tauopathy, compared to controls.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Using a fluorescence-based reporter of de novo TE insertion, Sun et al. found that pan-neuronal expression of transgenic human tau induced transposition in adult neurons of the Drosophila brain.
“Using a fluorescence-based reporter of de novo TE insertion (Li et al. 2013), Sun et al. (2018) found that pan-neuronal expression of transgenic human tau induced transposition in adult neurons of the Drosophila brain.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
The Results section, “Active transposable element mobilization in neurons of tau transgenic Drosophila” (page unavailable), reports increased mobilization in adult flies using a GFP-based insertion reporter. But it explicitly says the reporter experiment used human tau driven in retinal neurons by GMR, rather than pan-neuronal tau expression. The Methods section, “Drosophila genetics” (page unavailable), confirms that distinction. (LLM, conf=0.91)
Experimental — accuracy not yet measuredAmong retrotransposons that are transcriptionally elevated in human AD and PSP, most are no longer active.
“Among retrotransposons that are transcriptionally elevated in human AD and PSP, most are no longer active (Guo et al. 2018, Sun et al. 2018).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
The Results section, “Aberrant transposable element transcription in human tauopathy” (page unavailable), reports elevated transposable-element transcripts in human AD and PSP, with endogenous retroviruses over-represented among those upregulated. It does not say that most of the elevated retrotransposons are no longer active; the passage about mobilization-capable elements concerns Drosophila, not the human samples. (LLM, conf=0.86)
Experimental — accuracy not yet measuredStudies in Drosophila indicate that the negative effects of tau on the lamin nucleoskeleton result in the decondensation of heterochromatin and a toxic, neuroinflammatory activation of retrotransposons.
“Studies in Drosophila indicate that the negative effects of tau on the lamin nucleoskeleton result in the decondensation of heterochromatin (Frost et al. 2014) and a toxic, neuroinflammatory activation of retrotransposons (Ochoa et al. 2023, Sun et al. 2018).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
The Results sections on Drosophila transposable-element transcripts and loss of silencing support tau-associated retrotransposon dysregulation and neuronal toxicity. The Discussion only speculates that endogenous retroviruses might contribute to neuroinflammation in human tauopathy; it does not establish neuroinflammatory activation in Drosophila. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTransposable element activation in AD is preferentially associated with tau pathology, consistently with findings from a Drosophila tauopathy model.
“Of note, transposable element activation in AD is preferentially associated with tau pathology, consistently with findings from a Drosophila tauopathy model [124].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [124]
The Results section, “Aberrant transposable element transcription in human tauopathy” (page unavailable), reports altered transposable-element expression in Alzheimer’s disease and another tauopathy, consistent with the Drosophila tau-model findings. It does not show that activation in Alzheimer’s disease is preferentially associated with tau pathology rather than other pathology. (LLM, conf=0.84)
Experimental — accuracy not yet measuredBoth interventions were found to reduce neurodegeneration, suggesting that the generation of new retrotransposon DNA copies is neurotoxic.
“Both interventions were found to reduce neurodegeneration, suggesting that the generation of new retrotransposon DNA copies is neurotoxic.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
Studies in tau transgenic Drosophila suggest that TEs are indeed capable of full retrotransposition.
“Studies in tau transgenic Drosophila suggest that TEs are indeed capable of full retrotransposition.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
Such transposition could be suppressed via caloric restriction or pharmacological blockage of reverse transcription.
“Such transposition could be suppressed via caloric restriction or pharmacological blockage of reverse transcription.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
In tau transgenic Drosophila, the nucleoside analog reverse transcriptase inhibitor (NRTI) 3TC reduces tau-induced retrotransposition and neurodegeneration.
“In tau transgenic Drosophila, the nucleoside analog reverse transcriptase inhibitor (NRTI) 3TC reduces tau-induced retrotransposition and neurodegeneration (Sun et al. 2018).”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
In addition to tau-induced decondensation of heterochromatin, brains of tau transgenic Drosophila were found to have significantly decreased levels of Piwi and piRNAs.
“In addition to tau-induced decondensation of heterochromatin, brains of tau transgenic Drosophila were found to have significantly decreased levels of Piwi and piRNAs.”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Sun et al. 2018
Several groups have independently detected elevated TE transcripts in human AD, adding to an intriguing phenomenon of TE dysregulation in neurodegenerative diseases.
“Several groups have independently detected elevated TE transcripts in human AD [122–124], adding to an intriguing phenomenon of TE dysregulation in neurodegenerative diseases [125–128].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [124]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting supplementary-figure references for cerebellum analysis
MinorThe results direct readers to Supplementary Fig. 8 for the cerebellum analysis, but the methods cite Supplementary Fig. 4 for the same analysis.
“cerebellum (Supplementary Fig. 8a, b)”
“We performed a similar analysis on cerebellum, which showed that 20 transposable elements have variable expression in Alzheimer’s disease, progressive supranuclear palsy, or control (Supplementary Fig. 4a, b, c, Supplementary Table 7).”
Drug-dose exception points to the wrong supplementary figure
MinorThe treatment methods say the exception to the 10 mM 3TC dose is in Supplementary Fig. 3, while the results place the dose-dependent 3TC experiments in Supplementary Fig. 7.
“3TC (Fisher, #50731692, 10 mM except in Supplementary Fig. 3)”
“3TC treatment significantly reduces tau-induced neuronal death (Fig. 6c), and significantly alleviates tau-induced locomotor deficits (Fig. 6d) in a dose-dependent manner (Supplementary Fig. 7a, b).”
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Connecting the dots between tau dysfunction and neurodegeneration
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Self-citationZamparini, A. L., Davis, M. Y., Malone, C. D., Vieira, E., Zavadil, J., Sachidanandam, R., Hannon, G. J., & Lehmann, R. (2011) · Development · doi:10.1242/dev.069187 · Cited by 121 · see citing works
Transcriptome-wide piRNA profiling in human brains of Alzheimer's disease
Qiu, W., Guo, X., Lin, X., Yang, Q., Zhang, W., Zhang, Y., Zuo, L., Zhu, Y., Li, C.-S. R., Ma, C., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.05.020 · Cited by 105 · see citing works
Human endogenous retroviruses and cancer
María, G.-C., Paola, I., Niki, K., Mariacarmela, S., Julià, B., & Rafael, R. (2016) · Cancer Biology & Medicine · doi:10.20892/j.issn.2095-3941.2016.0080 · Cited by 100 · see citing works
Inhibition of human endogenous retrovirus-K by antiretroviral drugs
Tyagi, R., Li, W., Parades, D., Bianchet, M. A., & Nath, A. (2017) · Retrovirology · doi:10.1186/s12977-017-0347-4 · Cited by 78 · see citing works
p53 prevents neurodegeneration by regulating synaptic genes
Merlo, P., Frost, B. E., Peng, S., Yang, Y. J., Park, P. J., & Feany, M. Β. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1419083111 · Cited by 76 · see citing works
Self-citationThird chromosome suppressor of position-effect variegation loci in Drosophila melanogaster
Reuter, G., Dorn, R., Wustmann, G., Friede, B., & Rauh, G. (1986) · Molecular and General Genetics MGG · doi:10.1007/bf00333281 · Cited by 72 · see citing works
Pélisson, A., Teysset, L., Chalvet, F., Kim, A., Prud'homme, N., Terzian, C., & Bucheton, A. (1997) · Genetica · doi:10.1023/a:1018336303298 · Cited by 65 · see citing works
A neuroprotective role for the DNA damage checkpoint in tauopathy
Khurana, V., Merlo, P., DuBoff, B., Fulga, T. A., Sharp, K. A., Campbell, S. D., Götz, J., & Feany, M. Β. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00778.x · Cited by 57 · see citing works
Terminator Oligo Blocking Efficiently Eliminates rRNA from Drosophila Small RNA Sequencing Libraries
Wickersheim, M. L., & Blumenstiel, J. P. (2013) · BioTechniques · doi:10.2144/000114102 · Cited by 53 · see citing works
Foroushani, A. B. K., Agrahari, R., Docking, R., Chang, L., Duns, G., Hudoba, M., Karsan, A., & Zare, H. (2017) · BMC Medical Genomics · doi:10.1186/s12920-017-0253-6 · Cited by 52 · see citing works
Self-citationBardai, F. H., Wang, L., Mutreja, Y., Yenjerla, M., Gamblin, T. C., & Feany, M. B. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.1550-17.2017 · Cited by 37 · see citing works
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Synergy between amyloid-β and tau in Alzheimer’s disease
Busche, M. A., & Hyman, B. T. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0687-6 · Cited by 1,242 · see citing works
The role of retrotransposable elements in ageing and age-associated diseases
Gorbunova, V., Seluanov, A., Mita, P., McKerrow, W., Fenyö, D., Boeke, J. D., Linker, S. B., Gage, F. H., Kreiling, J. A., Petrashen, A. P., et al. (2021) · Nature · doi:10.1038/s41586-021-03542-y · Cited by 457 · see citing works
Tam, O. H., Rozhkov, N. V., Shaw, R., Kim, D., Hubbard, I., Fennessey, S., Propp, N., Phatnani, H., Kwan, J., Sareen, D., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.09.066 · Cited by 327 · see citing works
“Other studies linked transposon activation in Alzheimer’s disease with tau aggregation and suggest these alterations accompany neuroinflammation and genomic instability (Guo et al., 2018; Sun et al., 2018).”
Emerging roles and functional mechanisms of PIWI-interacting RNAs
Wang, X., Ramat, A., Simonelig, M., & Liu, M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00528-0 · Cited by 285 · see citing works
Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies
Chang, C.-W., Shao, E., & Mucke, L. (2021) · Science · doi:10.1126/science.abb8255 · Cited by 263 · see citing works
“The suppression of neurodegeneration and locomotor abnormalities in a fruit fly tauopathy model by treatment with a reverse transcriptase inhibitor (100) provides additional support for the potential importance of this mechanism.”
BackgroundLoss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons
Liu, E. Y., Russ, J., Cali, C. P., Phan, J. M., Amlie-Wolf, A., & Lee, E. B. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.003 · Cited by 231 · see citing works
“Tau expression in Drosophila promotes neurodegeneration in part due to transposable elements, and pathologic tau has been associated with expression of transposable elements in Alzheimer’s disease tissues (Guo et al., 2018; Sun et al., 2018).”
BackgroundEarly neuronal accumulation of DNA double strand breaks in Alzheimer’s disease
Shanbhag, N. M., Evans, M. D., Mao, W., Nana, A. L., Seeley, W. W., Adame, A., Rissman, R. A., Masliah, E., & Mucke, L. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0723-5 · Cited by 214 · see citing works
“Several recent studies have demonstrated an increase in the level of transposable elements in Alzheimer’s disease and other neurodegenerative tauopathies [26, 107].”
Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy
Jiang, L., Lin, W., Zhang, C., Ash, P. E. A., Verma, M., Kwan, J., van Vliet, E., Yang, Z., Cruz, A. L., Boudeau, S., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.07.038 · Cited by 177 · see citing works
“Such changes might be expected, as tau pathology is known to induce changes in DNA function and structure (Cornelison et al., 2019; Frost et al., 2016; Sun et al., 2018).”
BackgroundLu, Y., Tan, L., & Wang, X. (2019) · Neuroscience Bulletin · doi:10.1007/s12264-019-00361-0 · Cited by 166 · see citing works
Losing DNA methylation at repetitive elements and breaking bad
Pappalardo, X. G., & Barra, V. (2021) · Epigenetics & Chromatin · doi:10.1186/s13072-021-00400-z · Cited by 153 · see citing works
The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing
Liu, Y., Tan, Y., Zhang, Z., Yi, M., Zhu, L., & Peng, W. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00397-x · Cited by 144 · see citing works
“Sun et al. [42] found that the tau deposition-induced absence of piwi and piRNAs and subsequent TE dysregulation seriously hinder the treatment of neurodegenerative diseases.”
BackgroundHuman endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors
Dembny, P., Newman, A. G., Singh, M., Hinz, M., Szczepek, M., Krüger, C., Adalbert, R., Dzaye, O., Trimbuch, T., Wallach, T., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.131093 · Cited by 134 · see citing works
Activation of human endogenous retroviruses and its physiological consequences
Dopkins, N., & Nixon, D. F. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00674-z · Cited by 122 · see citing works
“Oocytes that arise from PGCs display activation of HERVK14–LTR14 LTRs 19 , and upon fertilization, the expression of HERV elements and host genes is largely coordinated by TFBs within HERVK14–LTR14, HERVK–LTR5Hs, HERVH–LTR7, HERV9–LTR12, HERVL–MLT2 and THE1A LTRs 19 (Fig.”
InfluentialA combined miRNA-piRNA signature to detect Alzheimer’s disease
Jain, G., Stuendl, A., Rao, P., Berulava, T., Pena Centeno, T., Kaurani, L., Burkhardt, S., Delalle, I., Kornhuber, J., Hüll, M., et al. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0579-2 · Cited by 121 · see citing works
Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders
Jönsson, M. E., Garza, R., Johansson, P. A., & Jakobsson, J. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.05.004 · Cited by 122 · see citing works
“Mechanistic studies in Drosophila models suggest that the activation of TEs is linked to Tau pathology [53,95].”
BackgroundResultInfluentialCalderón‐Garcidueñas, L., Herrera-Soto, A., Jury, N., Maher, B. A., González-Maciel, A., Reynoso-Robles, R., Ruiz-Rudolph, P., van Zundert, B., & Varela‐Nallar, L. (2020) · Environmental Research · doi:10.1016/j.envres.2020.109226 · Cited by 116 · see citing works
Jönsson, M. E., Brattås, P. L., Gustafsson, C., Petri, R., Yudovich, D., Pircs, K., Verschuere, S., Madsen, S., Hansson, J., Larsson, J., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11150-8 · Cited by 113 · see citing works
Kuo, M., Liu, S. C.-H., Hsu, Y.-F., & Wu, R. (2021) · Journal of Biomedical Science · doi:10.1186/s12929-021-00775-x · Cited by 96 · see citing works
Rexach, J. E., Polioudakis, D., Yin, A., Swarup, V., Chang, T. S., Nguyen, T., Sarkar, A., Chen, L., Huang, J., Lin, L.-C., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108398 · Cited by 94 · see citing works
“This is particularly salient based upon the recent observation that pathological tau drives chromatin destabilization (Guo et al., 2018; Sun et al., 2018), a known source of endogenous dsRNA that can activate Ifih1 (MDA5) and trigger an IFN response outside of the CNS (Ahmad et al.”
BackgroundThe Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases
Qu, L., Pan, C., He, S., Lang, B., Gao, G.-D., Wang, X., & Wang, Y. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00121 · Cited by 77 · see citing works
Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons
Moruno-Manchon, J. F., Lejault, P., Wang, Y., McCauley, B. S., Honarpisheh, P., Morales‐Scheihing, D., Singh, S. S., Dang, W., Kim, N., Urayama, A., et al. (2020) · eLife · doi:10.7554/elife.52283 · Cited by 80 · see citing works
Tissue-specific usage of transposable element-derived promoters in mouse development
Miao, B., Fu, S., Lyu, C., Gontarz, P. M., Wang, T., & Zhang, B. (2020) · Genome biology · doi:10.1186/s13059-020-02164-3 · Cited by 81 · see citing works
Activation of endogenous retroviruses during brain development causes an inflammatory response
Jönsson, M. E., Garza, R., Sharma, Y., Petri, R., Södersten, E., Johansson, J. G., Johansson, P. A., Atacho, D. A., Pircs, K., Madsen, S., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106423 · Cited by 80 · see citing works
“This increases our understanding of the consequences of ERV activation in the brain and provides new mechanistic insights opening up for further research into the role of ERVs and other TEs in various brain disorders.”
Current directions in tau research: Highlights from Tau 2020
Sexton, C. E., Snyder, H. M., Beher, D., Boxer, A. L., Brannelly, P., Brion, J., Buée, L., Cacace, A. M., Chételat, G., Citron, M., et al. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12452 · Cited by 78 · see citing works
Self-citationRamirez, P., Zuniga, G., Sun, W., Beckmann, A., Ochoa, E., DeVos, S. L., Hyman, B., Chiu, G., Roy, E. R., Cao, W., et al. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2021.102181 · Cited by 79 · see citing works
Self-citationModeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming
Sun, Z., Kwon, J.-S., Ren, Y., Chen, S., Walker, C. K., Lu, X., Cates, K., Karahan, H., Sviben, S., Fitzpatrick, J. A. J., et al. (2024) · Science · doi:10.1126/science.adl2992 · Cited by 77 · see citing works
“It was previously shown that dysregulation of retrotransposon elements (RTEs) in aging may trigger inflammatory responses (86–88) and suppression of RTE was shown to reduce tau activation and tau-induced neurotoxicity in tau transgenic Drosophila (77).”
TransposonUltimate: software for transposon classification, annotation and detection
Riehl, K., Riccio, C., Miska, E. A., & Hemberg, M. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac136 · Cited by 78 · see citing works
“Studying TEs is highly relevant for understanding evolutionary processes [9], developmental biology, gene regulation, and many diseases called transposonpathies such as subtypes of haemophilia, immunodeficiency, cancer and Alzheimer’s disease [10, 11, 12].”
BackgroundA critical appraisal of tau‐targeting therapies for primary and secondary tauopathies
Imbimbo, B. P., Ippati, S., Watling, M., & Balducci, C. (2021) · Alzheimer s & Dementia · doi:10.1002/alz.12453 · Cited by 72 · see citing works
Chénais, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052551 · Cited by 75 · see citing works
Chang, Y.-H., & Dubnau, J. (2019) · Current Biology · doi:10.1016/j.cub.2019.07.071 · Cited by 68 · see citing works
“It also is worth note that RTE/ERV induction has been reported in Drosophila tau ND models as well as in Alzheimer’s disease patient tissue [67, 68].”
Nitta, Y., & Sugie, A. (2022) · Fly · doi:10.1080/19336934.2022.2087484 · Cited by 74 · see citing works
“These findings indicate an increased transcription of genes and transposable elements that should be inactivated in heterochromatin, not only in the fly model but also in patients with AD and PSP [102,103].”
BackgroundPathogenic tau–induced transposable element–derived dsRNA drives neuroinflammation
Ochoa, E., Ramirez, P., Gonzalez, E., De Mange, J., Ray, W. J., Bieniek, K. F., & Frost, B. (2023) · Science Advances · doi:10.1126/sciadv.abq5423 · Cited by 73 · see citing works
“Similar to previous studies in which pan-neuronal knockdown of Su(var)205 or Su(var)3-9 is sufficient to drive neurodegeneration ( 6 ), we find that pan-neuronal RNAi-mediated reduction of rhino is sufficient to drive neurodegeneration in the adult Drosophila brain based on TUNEL (fig.”
InfluentialSelf-citationRepetitive elements in aging and neurodegeneration
Copley, K. E., & Shorter, J. (2023) · Trends in Genetics · doi:10.1016/j.tig.2023.02.008 · Cited by 70 · see citing works
“Some studies in this area have been conducted, but have been limited by small sample sizes [17,50,69,72,73,75,87,90,91,161,162].”
BackgroundInfluentialNon-coding RNA in the wiring and remodeling of neural circuits
Soutschek, M., & Schratt, G. M. (2023) · Neuron · doi:10.1016/j.neuron.2023.04.031 · Cited by 72 · see citing works
PIWI Proteins and piRNAs in the Nervous System.
Kim, K. W. (2019) · Europe PMC (PubMed Central) · doi:10.14348/molcells.2019.0241 · Cited by 69 · see citing works
“One of the potential pathological mechanisms of tauopathy is related to PIWI/piRNA regulation (Sun et al., 2018).”
BackgroundADAR2 mislocalization and widespread RNA editing aberrations in C9orf72-mediated ALS/FTD
Moore, S. R., Alsop, E. B., Lorenzini, I., Starr, A., Rabichow, B. E., Mendez, E. F., Levy, J. L., Burciu, C., Reiman, R. A., Chew, J., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-01999-w · Cited by 68 · see citing works
Hanna, R., Flamier, A., Barabino, A., & Bernier, G. (2021) · Nature Communications · doi:10.1038/s41467-021-22129-9 · Cited by 71 · see citing works
Endogenous retroviruses in development and health
Wang, J., Lu, X., Zhang, W., & Liu, G. (2023) · Trends in Microbiology · doi:10.1016/j.tim.2023.09.006 · Cited by 68 · see citing works
Melatonin ameliorates tau-related pathology via the miR-504-3p and CDK5 axis in Alzheimer’s disease
Chen, D., Lan, G., Li, R., Mei, Y., Shui, X., Gu, X., Wang, L., Zhang, T., Gan, C., Xia, Y., et al. (2022) · Translational Neurodegeneration · doi:10.1186/s40035-022-00302-4 · Cited by 68 · see citing works
Microglia: Friend and foe in tauopathy
Odfalk, K. F., Bieniek, K. F., & Hopp, S. C. (2022) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2022.102306 · Cited by 60 · see citing works
Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target
Oakley, S. S., Maina, M. B., Marshall, K. E., Al‐Hilaly, Y. K., Harrington, C., Wischik, C. M., & Serpell, L. C. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.590754 · Cited by 57 · see citing works
“For example, tau pathology has been shown to impair nucleocytoplasmic transport in AD and frontotemporal dementia (41, 42), induce nuclear envelope invagination in AD (43, 44), induce neurodegeneration through global chromatin relaxation (45), and transposable element dysregulation in AD (46).”
BackgroundBrain Somatic Mutation in Aging and Alzheimer's Disease
Miller, M. B., Reed, H., & Walsh, C. A. (2021) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-121520-081242 · Cited by 56 · see citing works
Autophagy facilitates age-related cell apoptosis—a new insight from senile cataract
Huang, J., Yu, W., He, Q., He, X., Yang, M. W., Chen, W., & Han, W. (2022) · Cell Death and Disease · doi:10.1038/s41419-021-04489-8 · Cited by 57 · see citing works
“Consequently, the age-related cell loss in postmitotic tissues can contribute to the occurrence of most senescence-associated degenerative diseases, including neurodegenerative Alzheimer’s or Parkinson’s disease [4], cardiomyopathy [5, 6], osteoarthritis [7], and senile cataract [8].”
BackgroundpiRNA-Guided CRISPR-like Immunity in Eukaryotes
Ophinni, Y., Palatini, U., Hayashi, Y., & Parrish, N. F. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.09.003 · Cited by 54 · see citing works
Somatic mutations in neurodegeneration: An update
Proukakis, C. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105021 · Cited by 53 · see citing works
“, 2018), and reduce tau-induced death mediated through transposable element mobilisation in a Drosophila model (Sun et al., 2018).”
Foroushani, A. B. K., Agrahari, R., Docking, R., Chang, L., Duns, G., Hudoba, M., Karsan, A., & Zare, H. (2017) · BMC Medical Genomics · doi:10.1186/s12920-017-0253-6 · Cited by 52 · see citing works
Self-citationFactors Regulating the Activity of LINE1 Retrotransposons
Protasova, M., Андреева, Т. В., & Rogaev, E. I. (2021) · Genes · doi:10.3390/genes12101562 · Cited by 51 · see citing works
LINE-1 activation in the cerebellum drives ataxia
Takahashi, T., Stoiljković, M., Song, E., Gao, X., Yasumoto, Y., Kudo, E., Carvalho, F., Kong, Y., Park, A., Shanabrough, M., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.08.011 · Cited by 54 · see citing works
Alzheimer’s disease and related tauopathies: disorders of disrupted neuronal identity
Frost, B. E. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.07.006 · Cited by 56 · see citing works
“In preclinical studies, pharmacological and/or genetic intervention at each node in the pathway that I outline above has been shown to effectively suppress tauinduced neurodegeneration in vivo [27,34,35,37,38,133,134].”
InfluentialSelf-citationTransposons, p53 and Genome Security
Tiwari, B., Jones, A. E., & Abrams, J. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.08.003 · Cited by 52 · see citing works
Yan, Z., Zhou, Z., Wu, Q., Chen, Z., Koo, E. H., & Zhong, S. (2020) · Current Biology · doi:10.1016/j.cub.2020.02.084 · Cited by 51 · see citing works
“Generally, it has been shown that transposon activity is elevated during aging and neuronal decline [44, 45] and, in AD, due to activation by pathogenic tau proteins [43, 46].”
BackgroundChang, Y.-H., & Dubnau, J. (2023) · Nature Communications · doi:10.1038/s41467-023-36649-z · Cited by 49 · see citing works
Phosphorylation regulates tau’s phase separation behavior and interactions with chromatin
Abasi, L. S., Elathram, N., Movva, M., Deep, A., Corbett, K. D., & Debelouchina, G. T. (2024) · Communications Biology · doi:10.1038/s42003-024-05920-4 · Cited by 49 · see citing works
“In other studies, loss of heterochromatin and transposable element activation have been observed in Alzheimer ’ s patient brain tissue and are correlated with NFT burden, further implicating pathological tau with aberrant gene expression 35,36 .”
The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology
Chesnokova, E., Beletskiy, A., & Kolosov, P. M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105847 · Cited by 48 · see citing works
Reactivated endogenous retroviruses promote protein aggregate spreading
Liu, S., Heumüller, S.-E., Hossinger, A., Müller, S. A., Buravlova, O., Lichtenthaler, S. F., Denner, P., & Vorberg, I. M. (2023) · Nature Communications · doi:10.1038/s41467-023-40632-z · Cited by 48 · see citing works
“Elevated ERV transcripts have been reported for AD 13,14 , PSP 15 , behavioral variant frontotemporal dementia 16 and sporadic Creutzfeldt-Jakob disease 65 .”
An old weapon with a new function: PIWI-interacting RNAs in neurodegenerative diseases
Huang, X., & Wong, G. (2021) · Translational Neurodegeneration · doi:10.1186/s40035-021-00233-6 · Cited by 47 · see citing works
“AD Depletion of piRNAs Depletion of piRNAs would drive transposable element dysregulation that leads to tauopathy neurodegeneration Drosophila [15]”
BackgroundInfluentialViruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases
Römer, C. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.648629 · Cited by 47 · see citing works
“This occurs, for example, between rabies virus and HERV-W (Lafon et al., 1992; Perron et al., 2001; Lafon et al., 2002) and between EBV and HERV-K18 (Sutkowski et al., 2001).”
BackgroundIntegrated analysis of the aging brain transcriptome and proteome in tauopathy
Mangleburg, C. G., Wu, T., Yalamanchili, H. K., Guo, C., Hsieh, Y.-C., Duong, D. M., Dammer, E. B., De Jager, P. L., Seyfried, N. T., Liu, Z., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00405-4 · Cited by 75 · see citing works
Retrotransposons as a Source of DNA Damage in Neurodegeneration
Pezé-Heidsieck, E., Bonnifet, T., Znaidi, R., Ravel‐Godreuil, C., Massiani-Beaudoin, O., Joshi, R. L., & Fuchs, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.786897 · Cited by 49 · see citing works
“As shown in Figure 1C , a full-length LINE-1 contains two open reading frames: ORF1 coding for ORF1p (an RNA binding protein) and ORF2 encoding ORF2p (with endonuclease, EN, and reverse transcriptase, RT, activity).”
BackgroundInfluentialTransposable elements in brain health and disease
Ahmadi, A., Toma, I. D., Vilor‐Tejedor, N., Ghamsari, M. R. E., & Sadeghi, I. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101153 · Cited by 46 · see citing works
Frost, B., & Dubnau, J. (2024) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-082823-020615 · Cited by 45 · see citing works
Self-citationNeuronal nuclear tau and neurodegeneration
Antón‐Fernández, A., Vallés‐Saiz, L., Ávila, J., & Hernández, F. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.07.015 · Cited by 44 · see citing works
Chang, Y., Keegan, R. M., Prazak, L., & Dubnau, J. (2019) · PLoS Biology · doi:10.1371/journal.pbio.3000278 · Cited by 43 · see citing works
Novel Targets for Alzheimer's Disease: A View Beyond Amyloid
Ray, W. J., & Buggia-Prévot, V. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-052919-120219 · Cited by 43 · see citing works
Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer’s disease
Islam, M. R., Nagakannan, P., Shcholok, T., Contu, F., Mai, S., Albensi, B. C., Bigio, M. R. D., Wang, J., Sharoar, M. G., Yan, R., et al. (2021) · Aging Cell · doi:10.1111/acel.13531 · Cited by 45 · see citing works
“These studies proposed that NL damage is a consequence of Tau hyperphosphorylation (Frost et al., 2014) and leads to aberrant gene expression (Cornelison et al., 2019; Sun et al., 2018).”
BackgroundTreiber, C. D., & Waddell, S. (2020) · Genome Research · doi:10.1101/gr.259200.119 · Cited by 43 · see citing works
Transposable elements and their role in aging
Александровна, Ю. Е., & Moskalev, A. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101881 · Cited by 41 · see citing works
Biotin rescues mitochondrial dysfunction and neurotoxicity in a tauopathy model
Lohr, K. M., Frost, B. E., Scherzer, C. R., & Feany, M. Β. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922392117 · Cited by 41 · see citing works
Self-citationConstitutive Heterochromatin in Eukaryotic Genomes: A Mine of Transposable Elements
Marsano, R. M., & Dimitri, P. (2022) · Cells · doi:10.3390/cells11050761 · Cited by 41 · see citing works
Neuroprotective Effects of PARP Inhibitors in Drosophila Models of Alzheimer’s Disease
Maggiore, A., Casale, A. M., Toscanelli, W., Cappucci, U., Rotili, D., Grieco, M., Gagné, J.-P., Poirier, G. G., d’Erme, M., & Piacentini, L. (2022) · Cells · doi:10.3390/cells11081284 · Cited by 40 · see citing works
“Growing evidence suggests a detrimental effect of TEs activity in neurodegenerative disorders including AD [95,97].”
BackgroundTransposable elements and Alzheimer’s disease pathogenesis
Evering, T. H., Marston, J. L., Gan, L., & Nixon, D. F. (2022) · Trends in Neurosciences · doi:10.1016/j.tins.2022.12.003 · Cited by 40 · see citing works
“In retrotranscriptomic studies in humans, an increase in HERV-H, -K, and -L family level expression was measured in RNAsequencing data of AD human postmortem cortex brain tissue compared with controls [4], and was confirmed by a separate group using the same publicly available data set [5].”
Wahl, D., Smith, M. E., McEntee, C. M., Cavalier, A. N., Osburn, S. C., Burke, S. D., Grant, R. A., Nerguizian, D., Lark, D. S., Link, C. D., et al. (2023) · Aging Cell · doi:10.1111/acel.13798 · Cited by 40 · see citing works
“Finally, given previous findings linking tau with TE activation in Alzheimer's disease (Guo et al., 2018; Sun et al., 2018), our finding that TE transcript levels increase with aging suggested that age- and pathology- related TE dysregulation might intersect.”
BackgroundResultInfluentialRole of piRNA biogenesis and its neuronal function in the development of neurodegenerative diseases
Sato, K., Takayama, K.-I., & Inoue, S. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1157818 · Cited by 41 · see citing works
Casier, K., Boivin, A., Carré, C., & Teysset, L. (2019) · Cells · doi:10.3390/cells8091108 · Cited by 37 · see citing works
When the infectious environment meets the AD brain
Ganz, T., Fainstein, N., & Ben-Hur, T. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00559-3 · Cited by 39 · see citing works
“TE dysregulation may contribute to neuronal death in tauopathies, a significant increase in HERVs transcripts was found in AD [109], and differential expression of several retrotransposons was observed in association with burden of neurofibrillary tangle in human AD brains [110].”
BackgroundDi Giorgio, E., & Xodo, L. E. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.917998 · Cited by 39 · see citing works
“RNA-seq analysis performed in tau and WT heads identified 50 and 60 transposable elements that are respectively significantly increased and decreased in tau transgenic model (137).”
BackgroundInfluentialNapoletano, F., Bravo, G. F., Voto, I. A. P., Santin, A., Celora, L., Campaner, E., Dezi, C., Bertossi, A., Valentino, E., Santorsola, M., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109694 · Cited by 37 · see citing works
A retrotransposon storm marks clinical phenoconversion to late-onset Alzheimer’s disease
Macciardi, F., Giulia Bacalini, M., Miramontes, R., Boattini, A., Taccioli, C., Modenini, G., Malhas, R., Anderlucci, L., Gusev, Y., Gross, T. J., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00580-w · Cited by 37 · see citing works
“Studies in Alzheimer’s disease, and other tauopathies such as progressive supranuclear palsy (PSP), have shown alterations in TE expression profiles that suggest a potential involvement in Taudependent pathological mechanisms leading to neurodegeneration [2, 100].”
BackgroundEndogenous Retroviruses in Nervous System Disorders
Gröger, V., Emmer, A., Staege, M. S., & Cynis, H. (2021) · Pharmaceuticals · doi:10.3390/ph14010070 · Cited by 37 · see citing works
Increased Alu RNA processing in Alzheimer brains is linked to gene expression changes
Cheng, Y., Saville, L., Gollen, B., Alvarez-Veronesi, A., Mohajerani, M. H., Joseph, J. T., & Zovoilis, A. (2021) · EMBO Reports · doi:10.15252/embr.202052255 · Cited by 35 · see citing works
“Available from: [https://celltypes.brain-map.org/rnaseq/human_ctx_sma rt-seq] based on (Tasic et al , 2018; Hodge et al , 2019).”
Bravo, J. I., Nozownik, S., Danthi, P. S., & Benayoun, B. A. (2020) · Development · doi:10.1242/dev.175786 · Cited by 34 · see citing works
“…pathologies, including cancer (Di Ruocco et al., 2018; Iskow et al., 2010; De Luca et al., 2015; Rodic ́ et al., 2014), AD (Guo et al., 2018; Sun et al., 2018) and TDP-43-mediated ailments (e.g. amyotrophic lateral sclerosis, frontotemporal lobar degeneration, etc.) (Krug et al., 2017; Li…”
BackgroundCellular senescence and neurodegeneration
Holloway, K., Neherin, K., Dam, K. U., & Zhang, H. (2023) · Human Genetics · doi:10.1007/s00439-023-02565-x · Cited by 40 · see citing works
Vallés-Saiz, L., Ávila, J., & Hernández, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241311144 · Cited by 35 · see citing works
“Thus, an increase in TE transcripts has been observed in a Drosophila model of mutant tau (13, 14).”
BackgroundInfluentialAwakening the dark side: retrotransposon activation in neurodegenerative disorders
Ochoa Thomas, E., Zuniga, G., Sun, W., & Frost, B. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.01.012 · Cited by 35 · see citing works
Self-citationJury, N., Abarzúa, S., Díaz, I. D. P., Guerra, M. V., Ampuero, E., Cubillos, P., Martínez, P., Herrera-Soto, A., Arredondo, C., Rojas, F., et al. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-0816-9 · Cited by 35 · see citing works
“Notably, evidence for aberrant expression of coding and non-coding genes, including repeat elements, has been reported in patients and in tau animal models of AD [28, 29, 65] that also display reduced H3K9me3 [26] or H3K9me2 staining signals [28, 29].”
Sullivan, A. C., Zuniga, G., Ramirez, P., Fernandez, R. A., Wang, C., Li, J., Davila, L., Pelton, K., Gomez, S., Sohn, C., et al. (2025) · npj Dementia · doi:10.1038/s44400-024-00001-z · Cited by 33 · see citing works
“The reverse transcriptase inhibitor 3TC effectively reduces retrotransposon activation and neurotoxicity in Drosophila 7 , mouse 11,12 , cell 11 , and brain spheroid 22 models of tauopathy and Alzheimer ’ s disease.”
InfluentialSelf-citationTau‐induced deficits in nonsense‐mediated mRNA decay contribute to neurodegeneration
Zuniga, G., Levy, S. A., Ramirez, P., Mange, J. D., Gonzalez, E. M., Gamez, M., & Frost, B. E. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12653 · Cited by 34 · see citing works
Self-citationTargeting epigenetics: A novel promise for Alzheimer’s disease treatment
Jeremic, D., Jiménez‐Díaz, L., & Navarro‐López, J. D. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102003 · Cited by 36 · see citing works
Tau; One Protein, So Many Diseases
Tabeshmehr, P., & Eftekharpour, E. (2023) · Biology · doi:10.3390/biology12020244 · Cited by 33 · see citing works
Roy, N., Haq, I., Ngo, J. C., Bennett, D. A., Teich, A. F., Jager, P. L. D., Olah, M., & Sher, F. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02835-6 · Cited by 35 · see citing works
“Intriguingly, tau burden is associated with extensive chromatin remodeling, loss of TE silencing, and its subsequent activation [31, 39, 42, 58, 116].”
Transposable element landscapes in aging Drosophila
Yang, N., Srivastav, S. P., Rahman, R., Ma, Q., Dayama, G., Li, S., Chinen, M., Lei, E. P., Rosbash, M., & Lau, N. C. (2022) · PLoS Genetics · doi:10.1371/journal.pgen.1010024 · Cited by 32 · see citing works
Licastro, F., & Porcellini, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147263 · Cited by 33 · see citing works
“Moreover, another investigation provided evidence that the tau protein promoted neuronal death in tauopathies by dysregulating TE [52].”
BackgroundResultInfluentialPiwi reduction in the aged niche eliminates germline stem cells via Toll-GSK3 signaling
Lin, K., Wang, W., Lin, C., Rastegari, E., Su, Y., Chang, Y.-T., Liao, Y., Chang, Y.-C., Pi, H., Yu, B.-Y., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16858-6 · Cited by 31 · see citing works
Casale, A. M., Liguori, F., Ansaloni, F., Cappucci, U., Finaurini, S., Spirito, G., Persichetti, F., Sanges, R., Gustincich, S., & Piacentini, L. (2021) · iScience · doi:10.1016/j.isci.2021.103702 · Cited by 33 · see citing works
“Growing evidence suggests a detrimental effect of TEs activity in neurodegenerative disorders (Chang and Dubnau, 2019; Douville et al., 2011; Fukuda et al., 2021; Guo et al., 2018; Kaneko et al., 2011; Krug et al., 2017; Li et al., 2012, 2015; Liu et al., 2019; Perron et al., 1997; Prudencio et al., 2017; Romano et al…”
BackgroundMethodInfluentialTDP-43 proteinopathy in ALS is triggered by loss of ASRGL1 and associated with HML-2 expression
Montojo, M. G., Fathi, S., Rastegar, C., Simula, E. R., Doucet-O’Hare, T. T., Cheng, Y.-H. H., Abrams, R. P. M., Pasternack, N., Malik, N., Bachani, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48488-7 · Cited by 31 · see citing works
“Transposable elements dysregulation is also a mediator of neuronal death in tauopathies 61 .”
BackgroundGiong, H.-K., Subramanian, M., Yu, K., & Lee, J.-S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168465 · Cited by 29 · see citing works
“Similarly, transposable element dysregulation was identified as a key mediator of neuronal death in tauopathies, where heterochromatin decondensation and reduction of piwi and piwi-interacting RNAs (piRNAs) drive transposable element dysregulation in tauopathy [137].”
BackgroundTau Stabilizes Chromatin Compaction
Rico, T., Gilles, M., Chauderlier, A., Comptdaer, T., Magnez, R., Chwastyniak, M., Drobecq, H., Pinet, F., Thuru, X., Buée, L., et al. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.740550 · Cited by 29 · see citing works
“Among them, dysregulation of transposable elements expression has been shown to be essential in mediating neuronal cell death (Sun et al., 2018).”
BackgroundFriend or foe: role of pathological tau in neuronal death
Wu, M., Chen, Z., Jiang, M. H., Bao, B., Li, D., Yin, X., Wang, X., Liu, D., & Zhu, L. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02024-z · Cited by 28 · see citing works
Transcriptome analyses reveal tau isoform-driven changes in transposable element and gene expression
Grundman, J., Spencer, B., Sarsoza, F., & Rissman, R. A. (2021) · PLOS ONE · doi:10.1371/journal.pone.0251611 · Cited by 27 · see citing works
“Notably, treatment of tau-transgenic Drosophila with reverse transcriptase inhibitors to suppress TEs can result in marked phenotypic improvement and reduced cell death, presenting a potentially exciting new avenue for therapeutic approaches [13].”
BackgroundMethodResultInfluentialDysregulation of Human Somatic piRNA Expression in Parkinson’s Disease Subtypes and Stages
Zhang, T., & Wong, G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052469 · Cited by 29 · see citing works
“These investigators further validated their findings via observing increased transcripts of the retroviral class of transposable elements in human AD tissues [63].”
Background
- Authors
- Sun, W., Samimi, H., Gamez, M., Zare, H., & Frost, B.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Texas State University (US)
- Corresponding author
- Frost, Bess
- Venue
- Nature Neuroscience
- Published
- 2018-07-23
- Volume
- 21
- Issue
- 8
- Pages
- 1038-1048
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6095477
- OpenAlex
- W2884899270
- Cited by
- 315
- References
- 68
- Citations by year
- 2026: 21 · 2025: 48 · 2024: 46 · 2023: 39 · 2022: 39 · 2021: 39 · 2020: 34 · 2019: 25 · 2018: 4 · 2017: 1
- FWCI
- 19.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- tauopathy, transposable elements, Piwi, neuronal cell death, neurodegeneration, endogenous retroviruses, Alzheimer's disease, progressive supranuclear palsy
- MeSH terms
- Alzheimer Disease, Animals, DNA Transposable Elements, Drosophila melanogaster, Gene Expression Regulation, Humans, Motor Activity, Neurons, Supranuclear Palsy, Progressive
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