Tau promotes neurodegeneration through global chromatin relaxation
Open accessAbstract
The microtubule-associated protein tau is involved in a number of neurodegenerative disorders, including Alzheimer's disease. Previous studies have linked oxidative stress and subsequent DNA damage to neuronal death in Alzheimer's disease and related tauopathies. Given that DNA damage can substantially alter chromatin structure, we examined epigenetic changes in tau-induced neurodegeneration. We found widespread loss of heterochromatin in tau transgenic Drosophila and mice and in human Alzheimer's disease. Notably, genetic rescue of tau-induced heterochromatin loss substantially reduced neurodegeneration in Drosophila. We identified oxidative stress and subsequent DNA damage as a mechanistic link between transgenic tau expression and heterochromatin relaxation, and found that heterochromatin loss permitted aberrant gene expression in tauopathies. Furthermore, large-scale analyses from the brains of individuals with Alzheimer's disease revealed a widespread transcriptional increase in genes that were heterochromatically silenced in controls. Our results establish heterochromatin loss as a toxic effector of tau-induced neurodegeneration and identify chromatin structure as a potential therapeutic target in Alzheimer's disease.
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- Findingown data
Heterochromatin-embedded LacZ and GFP reporters were silenced in controls but expressed in tau transgenic Drosophila brains.
“These reporters were silenced in controls, but were expressed in tau transgenic Drosophila brains (Fig. 1e).”
Quote in the paperSubstantial claim - Findingown data
Total levels of H3K9me2 and HP1α were significantly decreased in tau transgenic Drosophila heads compared to controls.
“We found that total levels of H3K9me2 and HP1α were significantly decreased in tau transgenic Drosophila heads compared to controls (Fig. 1a, b).”
Quote in the paperSubstantial claim - Findingown data
Transgenic expression of tauWT or tauE14 also activated heterochromatin-embedded reporter expression in Drosophila.
“Transgenic expression of tauWT or tauE14 also activated reporter expression in Drosophila (Supplementary Fig. 1e).”
Quote in the paperSubstantial claim - Findingown data
Neuronal expression of tauWT or tauE14 reduced H3K9me2 and HP1α levels.
“Neuronal expression of tauWT or tauE14 reduced H3K9me2 and HP1α levels (Supplementary Fig. 1b, c)”
Quote in the paperSubstantial claim - Findingown data
The extent of heterochromatin loss caused by expression of wild type or pseudohyperphosphorylated tau correlated with their respective toxicities.
“The extent of heterochromatin loss caused by expression of wild type or pseudohyperphosphorylated tau correlated with their respective toxicities.”
Quote in the paperSubstantial claim
- Findingown data
Loss of ash1 or NURF complex function in tau transgenic flies significantly increased H3K9me2 and HP1α chromocenter labeling.
“Total H3K9me2 and HP1α levels (Fig. 2a, b, Supplementary Fig. 1f, g) and H3K9me2 and HP1α chromocenter labeling (Fig. 2c) were significantly increased in tau transgenic flies harboring a loss of function mutation in ash1 or RNAi targeted to NURF301.”
Quote in the paperSubstantial claim - Findingown data
Whole head homogenates from Trxr-1 and Sod2 mutant flies had increased activation of the heterochromatin-embedded reporter in the brain.
“and increased activation of the heterochromatin-embedded reporter in the brain (Fig. 3g, h)”
Quote in the paperSubstantial claim - Findingown data
70% of β-galactosidase positive foci in tau transgenic Drosophila were positive for cleaved PARP.
“70% of β–galactosidase positive foci were positive for cleaved PARP, a marker of caspase activation21 (Fig. 1g).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Williams, D.W., Kondo, S., Krzyzanowska, A., Hiromi, Y. & Truman, J.W. Local caspase activity directs engulfment of dendrites during pruning. Nat. Neurosci. 9, 1234–1236 (2006). source
- Findingown data
Mutant Su(var)3-9 and Su(var)205 transgenes were not toxic in the absence of tau.
“Importantly, mutant Su(var)3-9 and Su(var)205 transgenes were not toxic in the absence of tau.”
Quote in the paperSubstantial claim - Findingown data
In tauopathy mice, ring-like perinucleolar chromocenter staining was significantly reduced for both H3K9me2 and HP1α.
“In tauopathy mice, however, ring-like perinucleolar chromocenter staining was significantly reduced for both H3K9me2 and HP1α (Fig. 5a-c)”
Quote in the paperSubstantial claim - Findingown data
Loss of ash1 or NURF complex function in tau transgenic flies significantly increased total H3K9me2 and HP1α levels.
“Total H3K9me2 and HP1α levels (Fig. 2a, b, Supplementary Fig. 1f, g) and H3K9me2 and HP1α chromocenter labeling (Fig. 2c) were significantly increased in tau transgenic flies harboring a loss of function mutation in ash1 or RNAi targeted to NURF301.”
Quote in the paperSubstantial claim - Findingown data
Neuronal overexpression of CycA or Rheb did not activate the heterochromatin-embedded reporter.
“or activate the heterochromatin-embedded reporter (data not shown)”
Quote in the paperSubstantial claim - Findingown data
Genetically restoring heterochromatin in tau transgenic flies reduced the number of PCNA positive foci by approximately 50%.
“and reduced the number of PCNA positive foci (Fig. 2f) by approximately 50%”
Quote in the paperSubstantial claim - Findingown data
RNAi-mediated reduction of Ago3 significantly suppressed the locomotor defects of tau transgenic Drosophila.
“RNAi mediated reduction of Ago3 also significantly suppressed the locomotor defects of tau transgenic Drosophila (Fig. 4h).”
Quote in the paperSubstantial claim - Findingown data
The locomotor deficit of tau transgenic Drosophila was significantly rescued by RNAi-mediated reduction of ash1 or NURF301.
“and this locomotor deficit was significantly rescued by RNAi-mediated reduction of ash1 or NURF301 (Fig. 2g).”
Quote in the paperSubstantial claim - Findingown data
Genetically restoring heterochromatin in tau transgenic flies suppressed neuronal apoptosis.
“We found that genetically restoring heterochromatin in tau transgenic flies suppressed neuronal apoptosis (Fig. 2e)”
Quote in the paperSubstantial claim - Findingown data
RNAi-mediated reduction of Ago3 in tau transgenic Drosophila brains resulted in significantly fewer apoptotic cells.
“We found significantly fewer apoptotic and PCNA-positive cells in tau transgenic Drosophila brains expressing either of two nonoverlapping RNAi lines targeted to Ago3 (Fig. 4f, g).”
Quote in the paperSubstantial claim - Findingown data
Tauopathy model flies harboring mutations in Su(var)3-9 and Su(var)205 had double the levels of neuronal apoptosis compared to tau expressed alone.
“Tauopathy model flies harboring mutations in Su(var)3-9 and Su(var)205 had double the levels of neuronal apoptosis (Fig. 2l)”
Quote in the paperSubstantial claim - Findingown data
Expression of the remaining five genes (CG40006, Dscam, Gprk1, IntS3, and Snap25) was unaffected by heterochromatin loss.
“However, expression of the remaining five genes (CG40006, Dscam, Gprk1, IntS3, and Snap25) was unaffected by heterochromatin loss.”
Quote in the paperSubstantial claim - Findingown data
Six genes (Ago3, CG15115, CG15661, Ir41a, nvd, and uif) were significantly upregulated in tau transgenic flies.
“Six of the genes (Ago3, CG15115, CG15661, Ir41a, nvd, and uif) were significantly upregulated in tau transgenic flies (Fig. 4c), as predicted.”
Quote in the paperSubstantial claim - Findingown data
Loss of function mutations in Su(var)205 or Su(var)3-9 significantly enhanced the locomotor deficits of tau transgenic Drosophila.
“Loss of function mutations in Su(var)205 or Su(var)3-9 also significantly enhanced the locomotor deficits of tau transgenic Drosophila (Fig. 2n).”
Quote in the paperSubstantial claim - Findingown data
The percent of DNA in comet tails was increased in Trxr-1 and Sod2 mutant brains.
“We observed an increase in the percent of DNA in comet tails in Trxr-1 and Sod2 mutant brains”
Quote in the paperSubstantial claim - Findingown data
Brains of Drosophila with RNAi-mediated neuronal knockdown of Su(var)205 or Su(var)3-9 were positive for PCNA.
“Brains of Drosophila with RNAi-mediated neuronal knockdown of Su(var)205 or Su(var)3-9 were positive for PCNA (Fig. 3k)”
Quote in the paperSubstantial claim - Findingown data
Genetically manipulating chromatin in the context of transgenic tau did not alter tau levels or the levels of disease-associated tau phosphoepitopes PHF1, AT270, or AT8.
“Genetically manipulating chromatin in the context of transgenic tau did not alter tau levels or the levels of disease-associated tau phosphoepitopes PHF1, AT270, or AT8 (Supplementary Fig. 1l)”
Quote in the paperSubstantial claim - Findingown data
Neuronal overexpression of CycA or Rheb did not reduce H3K9me2 or HP1α levels.
“Neuronal overexpression of CycA or Rheb, two proteins known to promote the cell cycle, did not reduce H3K9me2 or HP1α levels (Fig. 3i, j)”
Quote in the paperSubstantial claim - Findingown data
pH2Av was present in the brains of Trxr-1 and Sod2 mutant flies but not in controls.
“Immunofluorescence indicated that pH2Av was present in the brains of Trxr-1481 and Sod2Δ02 mutant flies (Fig. 3a, b), but not in controls.”
Quote in the paperSubstantial claim - Findingown data
Mutation of Su(var)3-9 or Su(var)205 caused additional loss of H3K9me2 and HP1α chromocenter labeling compared to tau expressed alone.
“caused additional loss of H3K9me2 and HP1α chromocenter labeling (Fig. 2j)”
Quote in the paperSubstantial claim - Findingown data
Whole head homogenates from Trxr-1 and Sod2 mutant flies had reduced levels of H3K9me2 and HP1α.
“Indeed, whole head homogenates from Trxr-1481 and Sod2Δ02 flies had reduced levels of H3K9me2 and HP1α (Fig. 3e, f)”
Quote in the paperSubstantial claim - Findingown data
60% of β-galactosidase positive foci in tau transgenic Drosophila were positive for PCNA.
“we found that 60% of β–galactosidase positive foci in tau transgenic Drosophila were also positive for proliferating cell nuclear antigen (PCNA) (Fig. 1h)”
Quote in the paperSubstantial claim - Findingown data
Reducing H3K9me2 and HP1α levels by expressing tau with heterozygous loss-of-function alleles of Su(var)3-9 or Su(var)205 further reduced H3K9me2 and HP1α levels compared to tau expressed alone.
“In the context of transgenic human tau, mutation of Su(var)3-9 or Su(var)205 further reduced H3K9me2 and HP1α levels (Fig. 2h, i, Supplementary Fig. 1j, k)”
Quote in the paperSubstantial claim - Findingown data
80% of β-galactosidase positive foci in tau transgenic Drosophila were also positive for AT8.
“80% of β–galactosidase positive foci in tau transgenic Drosophila were also positive for a disease-associated tau phosphoepitope (AT8) (Fig. 1f)”
Quote in the paperNot a substantial claim - Findingown data
Tau transgenic Drosophila had a significant decrease in locomotor activity at ten days of age compared to control.
“Tau transgenic Drosophila had a significant decrease in locomotor activity at ten days of age compared to control”
Quote in the paperSubstantial claim - Findingown data
Tau transgenic Drosophila had similar mRNA levels of ash1, NURF301, and NURF38 compared to control.
“Tau transgenic Drosophila had similar mRNA levels of ash1, NURF301, and NURF38 compared to control”
Quote in the paperSubstantial claim - Findingown data
RNAi-mediated reduction of Ago3 in tau transgenic Drosophila brains resulted in significantly fewer PCNA-positive cells.
“We found significantly fewer apoptotic and PCNA-positive cells in tau transgenic Drosophila brains expressing either of two nonoverlapping RNAi lines targeted to Ago3 (Fig. 4f, g).”
Quote in the paperSubstantial claim - Findingown data
Mutation of Su(var)3-9 or Su(var)205 increased expression of the heterochromatin-embedded reporter compared to tau expressed alone.
“and increased expression of the heterochromatin-embedded reporter (Fig. 2k) compared to tau expressed alone”
Quote in the paperSubstantial claim - Findingown data
Ago3 protein levels were increased over 4-fold in tau transgenic Drosophila heads compared to control.
“Consistent with increased transcription, Ago3 protein levels were increased over 4-fold in tau transgenic Drosophila heads compared to control (Fig. 4d, e).”
Quote in the paperSubstantial claim - Findingown data
Only those genes with no to low baseline levels of transcription in controls are upregulated in tau transgenic Drosophila and in human AD.
“Notably, we found that only those genes with no to low baseline levels of transcription in controls are upregulated in tau transgenic Drosophila and in human AD.”
Quote in the paperSubstantial claim - Findingown data
Immunofluorescence revealed a widespread increase in PIWIL1 staining in AD hippocampal neurons.
“Immunofluorescence also revealed a widespread increase in PIWIL1 staining in AD hippocampal neurons (Fig. 6b).”
Quote in the paperSubstantial claim - Findingown data
Over one third of the genes that are heterochromatic and expressed at low levels in control hippocampal neurons were expressed at least 50% higher in AD, including PIWIL1 and UGT1A10.
“Notably, over one third of the genes that are heterochromatic and expressed at low levels in control hippocampal neurons were expressed at least 50% higher in AD, including PIWIL1 and UGT1A10 (Fig. 6g, genes listed in Supplementary Dataset 2)”
Quote in the paperSubstantial claim - Findingown data
Genetic reduction of Ago3 suppressed tau neurotoxicity in Drosophila.
“Genetic reduction of Ago3 suppressed tau neurotoxicity in Drosophila”
Quote in the paperSubstantial claim - Findingown data
H3K9me2 was significantly depleted in human AD neurons.
“We found that H3K9me2 was significantly depleted in human AD neurons (Fig. 6e, f).”
Quote in the paperSubstantial claim - Findingown data
For HP1α, diffuse staining was restricted to pyramidal neurons in AD brains that were positive for AT8.
“For HP1α, diffuse staining was restricted to pyramidal neurons in AD brains that were positive for a disease-associated tau phosphoepitope (AT8)”
Quote in the paperSubstantial claim - Findingown data
The list of genes with increased expression in AD reveals pluripotency-associated genes such as POU1F1, NOG, and NR5A2.
“Indeed, the list of genes with increased expression in AD reveals pluripotency-associated genes such as POU1F1, NOG, and NR5A2.”
Quote in the paperSubstantial claim - Findingown data
The chi-square test indicated that the most significant transcriptional increase in AD was for genes classified as heterochromatic and expressed at low levels in control.
“The chi-square test indicated that the most significant transcriptional increase in AD was for genes classified as heterochromatic and expressed at low levels in control (Fig. 6i).”
Quote in the paperSubstantial claim - Findingown data
PIWIL1 levels were significantly increased in FACS-purified neuronal nuclei from human AD brains compared to controls; geometric mean relative to CYC1 was 0.054 (s.e.m. = 0.022) in control versus 0.216 (s.e.m. = 0.088) in AD (n = 6 brains, p < 0.05 Wilcoxon Rank-Sum).
“The geometric mean of PIWIL1 levels relative to the endogenous control gene CYC1 were 0.054 (s.e.m. = 0.022) in control brains, versus 0.216 (s.e.m. = 0.088) in AD brains (n = 6 brains, p < 0.05 Wilcoxon Rank-Sum).”
Quote in the paperSubstantial claim - Findingown data
In AD peripheral blood mononuclear cells, 34.3% of genes that are heterochromatically silenced in control peripheral blood mononuclear cells were expressed at least 50% higher in AD.
“Similar to AD brain, 34.3% of genes that are heterochromatically silenced in control peripheral blood mononuclear cells were expressed at least 50% higher in AD (genes listed in Supplementary Dataset 3)”
Quote in the paperSubstantial claim - Findingown data
In AD peripheral blood mononuclear cells, only 17.0% of silenced genes in euchromatin were expressed at least 50% higher in AD.
“while only 17.0% of silenced genes in euchromatin were expressed at least 50% higher in AD (Supplementary Fig. 3h)”
Quote in the paperSubstantial claim - Findingown data
Oxidative stress caused heterochromatin loss in our Drosophila tauopathy model.
“Since oxidative stress caused heterochromatin loss in our Drosophila tauopathy model”
Quote in the paperSubstantial claim - Findingnone given
Heterochromatin loss and aberrant gene expression are conserved among Drosophila, mouse, and human tauopathy.
“Heterochromatin loss and aberrant gene expression are conserved among Drosophila, mouse, and human tauopathy”
Quote in the paperSubstantial claim - Findingown data
Pathway analysis using PANTHER indicated that genes associated with developmental processes were significantly overrepresented in the list of genes that were heterochromatically silenced in controls and expressed at least 50% higher in AD.
“Pathway analysis using the PANTHER Classification System indicated that genes associated with developmental processes were significantly overrepresented in the list of genes that were heterochromatically silenced in controls and expressed at least 50% higher in AD (Supplementary Table 1).”
Quote in the paperSubstantial claim - Findingown data
The fourth principal component assigned AD hippocampal neurons, severe AD hippocampi, and fetal brains to the same principal component.
“The first principal component that could not be trivially explained by different experimental conditions is the fourth, which assigned AD hippocampal neurons, severe AD hippocampi, and fetal brains to the same principal component (Supplementary Fig. 3e).”
Quote in the paperSubstantial claim - Findingown data
Significant large-scale gene expression changes were not observed in an unrelated liver disease.
“Significant large-scale gene expression changes were not observed in an unrelated liver disease (Supplementary Fig. 3c, d)”
Quote in the paperSubstantial claim - Findingnone given
Widespread changes in heterochromatic gene expression are conserved in the blood as well as the brain in patients with AD.
“Furthermore, widespread changes in heterochromatic gene expression are conserved in the blood as well as the brain in patients with AD”
Quote in the paperNot a substantial claim - Findingown data
Only 13% of euchromatic genes with low expression were expressed at least 50% higher in AD.
“while only 13% of euchromatic genes with low expression were expressed at least 50% higher in AD (Fig. 6h).”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin defects are a general feature of tau-induced toxicity.
“indicating that heterochromatin defects are a general feature of tau-induced toxicity”
Quote in the paperSubstantial claim - Interpretationown data
Loss of H3K9me2 and HP1α in tauopathy was not due to transcriptional changes in Su(var)3-9 or Su(var)205.
“indicating that loss of H3K9me2 and HP1α in tauopathy was not due to transcriptional changes in these genes”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin defects are downstream of aberrant tau phosphorylation.
“and are downstream of aberrant tau phosphorylation”
Quote in the paperSubstantial claim - Interpretationreasoning
Heterochromatin loss is not a result of general cellular toxicity.
“these data also indicate that heterochromatin loss is not a result of general cellular toxicity.”
Quote in the paperSubstantial claim - Interpretationown data
Baseline levels of gene transcription control how a gene embedded within heterochromatin will respond to heterochromatin loss.
“These data suggest that baseline levels of gene transcription control how a gene embedded within heterochromatin will respond to heterochromatin loss.”
Quote in the paperSubstantial claim - Premisecitation
The five genes unaffected by heterochromatin loss are classified as moderately to highly expressed in Drosophila heads despite their heterochromatic environment.
“These five genes are classified as moderately to highly expressed (modEncode Project31) in Drosophila heads despite their heterochromatic environment”
Quote in the paperSubstantial claim0 of 1 sources checked- cites modEncode Project31
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Heterochromatin loss in tau transgenic Drosophila is downstream of tau phosphorylation.
“These results suggest that heterochromatin loss in tau transgenic Drosophila is downstream of tau phosphorylation”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin loss is upstream of aberrant cell cycle activation in neurons.
“suggesting that heterochromatin loss is indeed upstream of aberrant cell cycle activation in neurons.”
Quote in the paperSubstantial claim - Interpretationown data
Oxidative stress can cause heterochromatin loss in tauopathy.
“supporting the idea that oxidative stress can cause heterochromatin loss in tauopathy.”
Quote in the paperSubstantial claim - Interpretationreasoning
Oxidative stress-induced DNA damage is upstream of heterochromatin loss in a sequence of cellular events that lead to aberrant cell cycle activation and subsequent neuronal apoptosis.
“Taken together, these data place oxidative stress-induced DNA damage upstream of heterochromatin loss in a sequence of cellular events that lead to aberrant cell cycle activation and subsequent neuronal apoptosis.”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin loss and aberrant gene expression are features of tauopathy that are conserved between Drosophila and mice.
“These data suggest that heterochromatin loss and aberrant gene expression are features of tauopathy that are conserved between Drosophila and mice.”
Quote in the paperSubstantial claim - Interpretationown data
Tau did not cause heterochromatin changes by altering expression of ash1, NURF301, or NURF38.
“suggesting that tau did not cause heterochromatin changes by altering expression of these genetic modifiers”
Quote in the paperSubstantial claim - Premisecitation
The six genes with increased expression in tau transgenic Drosophila are classified as heterochromatically silenced, with no to low baseline expression in Drosophila heads.
“while the six genes with increased expression in tau transgenic Drosophila are classified as heterochromatically silenced, with no to low baseline expression in Drosophila heads (Fig. 4c).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites modEncode Project31
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Aberrant gene expression resulting from heterochromatin relaxation is a toxic mediator of tauopathy.
“These data strongly suggest that aberrant gene expression resulting from heterochromatin relaxation is a toxic mediator of tauopathy.”
Quote in the paperSubstantial claim - Interpretationown data
Suppression or enhancement of tau toxicity by chromatin manipulation is not simply a result of altered tau expression.
“and that suppression or enhancement of tau toxicity is not simply a result of altered tau expression.”
Quote in the paperSubstantial claim - Premisecitation
JNPL3 mice express human tau carrying the FTDP-17 mutation P301L (tauP301L).
“JNPL3 mice express human tau carrying the FTDP-17 mutation P301L (tauP301L).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405 (2000). source
- Interpretationown data
Heterochromatin loss is a cause of cell cycle activation and neuronal death in tauopathy.
“directly implicating heterochromatin loss as a cause of cell cycle activation and neuronal death in tauopathy.”
Quote in the paperSubstantial claim - Interpretationown data
Tau-induced heterochromatin loss only affects the expression of genes that are normally transcriptionally silenced by heterochromatin.
“Thus, tau-induced heterochromatin loss only affects the expression of genes that are normally transcriptionally silenced by heterochromatin.”
Quote in the paperSubstantial claim - Interpretationown data
Cell cycle activation does not cause widespread heterochromatin loss.
“suggesting that cell cycle activation does not cause widespread heterochromatin loss.”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin loss plays a causal role in tau-induced neurotoxicity in vivo.
“In total, these genetic data imply that heterochromatin loss plays a causal role in tau-induced neurotoxicity in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
Suppression of tau-induced toxicity by Ago3 RNAi was not due to decreased tau expression or alterations in tau phosphorylation.
“indicating that suppression of tau-induced toxicity was not due to decreased tau expression or alterations in tau phosphorylation.”
Quote in the paperSubstantial claim - Interpretationown data
DNA damage is one mechanism whereby pathologic tau causes global heterochromatin relaxation.
“damage is one mechanism whereby pathologic tau causes global heterochromatin relaxation”
Quote in the paperSubstantial claim - Study design and conductown data
Western blots with neuron- (NeuN) and astrocyte-specific (S100β) antibodies confirmed the purity of each nuclear population.
“Western blots with neuron- (NeuN) and astrocyte-specific (S100β) antibodies confirmed the purity of each nuclear population (Fig. 6d).”
Quote in the paperSubstantial claim - Study design and conductown data
RT-PCR confirmed RNAi-mediated knockdown of Ago3 in the brains of transgenic flies.
“RT-PCR confirmed RNAi-mediated knockdown of Ago3 in the brains of transgenic flies (Supplementary Fig. 2c).”
Quote in the paperSubstantial claim - Interpretationreasoning
Oxidative stress-induced DNA damage is one mechanism whereby pathologic tau causes global heterochromatin relaxation.
“Our data suggest that oxidative stress-induced DNA damage is one mechanism whereby pathologic tau causes global heterochromatin relaxation”
Quote in the paperSubstantial claim - Interpretationown data
Ago3/PIWIL1-mediated piRNA biogenesis and subsequent transposable element control are deregulated in tauopathy.
“These data suggest that Ago3/PIWIL1-mediated piRNA biogenesis and subsequent transposable element control are deregulated in tauopathy.”
Quote in the paperSubstantial claim - Study design and conductown data
Quantitative methods validated the loss of H3K9me2 and increase of PIWIL1 levels in AD in age-, gender-, and postmortem interval-matched cases and controls.
“We next used quantitative methods to validate the loss of H3K9me2 and increase of PIWIL1 levels in AD in age-, gender-, and postmortem interval-matched cases and controls.”
Quote in the paperSubstantial claim - Interpretationown data
There is a major global shift in gene expression in AD toward a more fetal state.
“consistent with a major global shift in gene expression in AD toward a more fetal state.”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatin loss is a toxic effector of tau-induced neurodegeneration.
“Our results establish heterochromatin loss as a toxic effector of tau-induced neurodegeneration”
Quote in the paperSubstantial claim - Interpretationown data
Loss of normal heterochromatin promotes tau-mediated neurodegeneration in vivo.
“We have found that loss of normal heterochromatin promotes tau-mediated neurodegeneration in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
Changes in heterochromatin present in AD brain are also present in peripheral blood.
“suggesting that changes in heterochromatin present in AD brain are also present in peripheral blood.”
Quote in the paperSubstantial claim - Interpretationown data
Heterochromatically silenced genes are transcriptionally more sensitive than active genes to changes in the local chromatin environment.
“it suggests that heterochromatically silenced genes are transcriptionally more sensitive than active genes to changes in the local chromatin environment”
Quote in the paperSubstantial claim - Interpretationown data
The results do not represent nonspecific effects of cellular toxicity.
“suggesting that our results do not represent nonspecific effects of cellular toxicity.”
Quote in the paperSubstantial claim - Study design and conductown data
RT-PCR confirmed knockdown of ash1, NURF301, and NURF38 mRNA levels in heads of transgenic flies.
“We used RT-PCR to confirm knockdown of ash1, NURF301, and NURF38 mRNA levels in heads of transgenic flies (Supplementary Fig. 1i).”
Quote in the paperSubstantial claim
- May combine two claims. 19
- Classified as probably not a substantial claim. 25
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationPan-neuronal transgenic expression of an FTDP-17 mutant form of human tau, tauR406W, in Drosophila causes progressive neurodegeneration and provides a well-characterized in vivo genetic model of tau neurotoxicity.
“Pan-neuronal transgenic expression of an FTDP-17 mutant form of human tau, tauR406W, in Drosophila causes progressive neurodegeneration and provides a well-characterized in vivo genetic model of tau neurotoxicity7,15,16.”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [7] Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006). source
The Introduction describes transgenic human or mutant tau expression in Drosophila as recapitulating progressive neurodegeneration, and the Results document age-dependent degeneration in tau-expressing flies. The methods identify a panneural expression driver. Our copy does not identify the flies showing these findings as expressing tauR406W, however; the Results explicitly name tauV337M for one genetic experiment. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [15] Wittmann, C.W. et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711–714 (2001). source
- cites [16] 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). May combine two claims.
PremisecitationComponents of the piRNA pathway are associated with stem cell self-renewal and are aberrantly expressed in several types of somatic tumors.
“components of the piRNA pathway are associated with stem cell self-renewal and are aberrantly expressed in several types of somatic tumors50”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [50] Juliano, C., Wang, J. & Lin, H. Uniting germline and stem cells: the function of Piwi proteins and the piRNA pathway in diverse organisms. Annu. Rev. Genet. 45, 447–469 (2011). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIncreased expression of a regulatory RNA has already been implicated in the pathogenesis of AD.
“Indeed, increased expression of a regulatory RNA has already been implicated in the pathogenesis of AD49.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Faghihi, M.A. et al. Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat. Med. 14, 723–730 (2008). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationTau is thought to protect DNA from oxidative damage.
“and is thought to protect DNA from oxidative damage46-48”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [46] Krylova, S.M. et al. Tau protein binds single-stranded DNA sequence specifically—the proof obtained in vitro with non-equilibrium capillary electrophoresis of equilibrium mixtures. FEBS Lett. 579, 1371–1375 (2005). source
- cites [47] Sjöberg, M.K., Shestakova, E., Mansuroglu, Z., Maccioni, R.B. & Bonnefoy, E. Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization. J. Cell Sci. 119, 2025–2034 (2006). source
- cites [48] Wei, Y. et al. Binding to the minor groove of the double-strand, tau protein prevents DNA from damage by peroxidation. PLoS ONE 3, e2600 (2008). source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductcitationNo statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported in previous publications.
“No statistical methods were used to predetermine sample sizes but our sample sizes are similar to those reported in previous publications 7,16,44.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [7] Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006). source
- cites [16] 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
- cites [44] DuBoff, B., Gotz, J. & Feany, M.B. Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75, 618–632 (2012). source
The Experimental Procedures (Immunoblotting; page unavailable) say immunoblots were repeated at least three times, but give no basis for comparing this paper’s sample sizes with those of the citing study. Searches for sample-size planning, sample counts, and comparisons with previous publications found no passage addressing that comparison. The statement about not predetermining sample sizes describes the citing authors’ own methods, not a claim this source can establish. (LLM, conf=0.70)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationEIFA4 and CYC1 were selected as internal controls for human RT-PCR based upon their stability in postmortem brain of AD patients.
“EIFA4 and CYC1 were selected as internal controls for human RT-PCR based upon their stability in postmortem brain of AD patients54.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [54] Penna, I. et al. Selection of candidate housekeeping genes for normalization in human postmortem brain samples. Int. J. Mol. Sci. 12, 5461–5470 (2011). source
The Results identify CYC1 as a stable reference gene in postmortem brain samples from AD patients and controls. The Discussion recommends CYC1 together with EIF4A2 for RT-qPCR normalization, but the claim names EIFA4 instead of EIF4A2. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationPathologic tau causes an increase in actin stabilization that inhibits association of the fission protein Drp1 with mitochondria, leading to mitochondrial elongation and production of reactive oxygen species.
“Pathologic tau causes an increase in actin stabilization18 that inhibits association of the fission protein Drp1 with mitochondria, leading to mitochondrial elongation and the production of reactive oxygen species44.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [18] Fulga, T.A. et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell Biol. 9, 139–148 (2007). source
- cites [44] DuBoff, B., Gotz, J. & Feany, M.B. Tau promotes neurodegeneration via DRP1 mislocalization in vivo. Neuron 75, 618–632 (2012). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn vitro and in cultured cells, tau binds the minor groove of the DNA double helix.
“In vitro and in cultured cells, tau binds the minor groove of the DNA double helix”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [46] Krylova, S.M. et al. Tau protein binds single-stranded DNA sequence specifically—the proof obtained in vitro with non-equilibrium capillary electrophoresis of equilibrium mixtures. FEBS Lett. 579, 1371–1375 (2005). source
- cites [47] Sjöberg, M.K., Shestakova, E., Mansuroglu, Z., Maccioni, R.B. & Bonnefoy, E. Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization. J. Cell Sci. 119, 2025–2034 (2006). source
- cites [48] Wei, Y. et al. Binding to the minor groove of the double-strand, tau protein prevents DNA from damage by peroxidation. PLoS ONE 3, e2600 (2008). source
The Discussion reports that tau binds the minor groove of double-stranded DNA, supported by competition assays described in the Results. The Introduction reports tau in cell nuclei and prior evidence of nuclear DNA binding, but the paper does not establish minor-groove binding in cultured cells. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim. May combine two claims.
Study design and conductown dataH3K9me2-based ChIP-sequencing was performed in biological duplicate and significantly H3K9me2 depleted genes were validated with quantitative PCR.
“To identify specific genes with reduced H3K9me2 levels, we performed H3K9me2-based ChIP-sequencing (ChIP-seq) in biological duplicate (Fig. 4a, http://genome.ucsc.edu30), and validated significantly H3K9me2 depleted genes with quantitative PCR (qPCR) (Fig. 4b).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [30] Kent, W.J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002). source
May combine two claims.
Findingown dataTau transgenic Drosophila had significantly reduced chromocenter labeling and diffusely distributed H3K9me2 and HP1α.
“Tau transgenic Drosophila, however, had significantly reduced chromocenter labeling, and instead had diffusely distributed H3K9me2 and HP1α (Fig. 1c, d, Supplementary Fig. 1d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLoss of ash1 function or RNAi-mediated reduction of NURF301 significantly silenced expression of the heterochromatin-embedded reporter in tau transgenic flies.
“Furthermore, loss of ash1 function or RNAi-mediated reduction of NURF301 significantly silenced expression of the heterochromatin-embedded reporter in tau transgenic flies (Fig. 2d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPIWIL1 levels were very low in control mice, and approximately double the levels of PIWIL1 staining were observed in motor neurons of tau transgenic mice.
“While PIWIL1 levels were very low in control mice, we observed approximately double the levels of PIWIL1 staining in motor neurons of tau transgenic mice (Fig. 5d).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn pyramidal hippocampal neurons from postmortem control brains, H3K9me2 was concentrated in perinucleolar chromocenters, whereas in AD H3K9me2 staining was diffuse.
“In pyramidal hippocampal neurons from postmortem control brains, H3K9me2 was concentrated in perinucleolar chromocenters. In AD, however, H3K9me2 staining was diffuse (Fig. 6a)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRNAi transgenes targeted to ash1, NURF301, and NURF38 were not toxic in the absence of tau, nor was loss of ash1 function.
“RNAi transgenes targeted to ash1, NURF301, and NURF38 were not toxic in the absence of tau, nor was loss of ash1 function.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataTauopathy model flies harboring mutations in Su(var)3-9 and Su(var)205 had double the levels of PCNA positive foci compared to tau expressed alone.
“and PCNA positive foci (Fig. 2m) compared to tau expressed alone.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTransgenic RNAi targeted to Ago3 did not affect levels of transgenic tau or tau phosphorylation.
“Transgenic RNAi targeted to Ago3 did not affect levels of transgenic tau or tau phosphorylation (Supplementary Fig. 2b)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAgo3/PIWIL1 was overexpressed in tau transgenic Drosophila and mice, and in human AD.
“Ago3/PIWIL1 was overexpressed in tau transgenic Drosophila and mice, and in human AD.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThere were eleven genes that were identified as significant in both experiments.
“There were eleven genes that were identified as significant in both experiments”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataFor the first experiment, we found 2,456 significant regions covering 167 different genes, and for the biological replicate we found 143 significant regions covering 22 different genes.
“For the first experiment, we found 2,456 significant regions covering 167 different genes, and for the biological replicate we found 143 significant regions covering 22 different genes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenSimilar results were obtained with both internal controls.
“Similar results were obtained with both internal controls.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataTau-induced heterochromatin loss permits aberrant gene expression that is coincident with tau neurotoxicity, cell cycle reentry, and subsequent apoptosis of postmitotic neurons.
“Together, these findings suggest that tau-induced heterochromatin loss permits aberrant gene expression that is coincident with tau neurotoxicity, cell cycle reentry, and subsequent apoptosis of postmitotic neurons.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataLoss of Trxr-1 or Sod2 function damages DNA.
“confirming that these genetic manipulations damage DNA (Fig. 3c, d).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationJNPL3 tau transgenic mice undergo progressive neurodegeneration and develop neurofibrillary tangles in the brain and spinal cord.
“These tau transgenic mice undergo progressive neurodegeneration, and develop neurofibrillary tangles in the brain and spinal cord35.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35] Lewis, J. et al. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat. Genet. 25, 402–405 (2000). source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningDysregulation of the piRNA pathway leads to loss of proliferative control.
“suggesting that dysregulation of the piRNA pathway leads to loss of proliferative control”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenExperiments were carried out in biological duplicates.
“Experiments were carried out in biological duplicates.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenEach data point is the result of at least three biological replicates each composed of three technical replicates.
“Each data point is the result of at least three biological replicates each composed of three technical replicates.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataOxidative stress causes DNA damage, heterochromatin loss and consequent aberrant gene expression in Drosophila.
“We have found that oxidative stress causes DNA damage, heterochromatin loss and consequent aberrant gene expression in Drosophila.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAgo3 regulates PIWI-interacting RNAs (piRNAs), a large class of highly conserved small noncoding RNAs that are responsible for silencing transposons.
“Ago3 regulates PIWI-interacting RNAs, or piRNAs, a large class of highly conserved small noncoding RNAs that are responsible for silencing transposons33,34.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Aravin, A. et al. A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442, 203–207 (2006). source
- cites [34] Girard, A., Sachidanandam, R., Hannon, G.J. & Carmell, M.A. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442, 199–202 (2006). source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData were collected and processed side by side in randomized order for all experiments.
“Data were collected and processed side by side in randomized order for all experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataFor experiments in mice and human tissue, sample sizes were based on power analysis calculations, which demonstrated that a 30% difference between 6 cases and controls will achieve a power of 80%.
“For experiments in mice and human tissue, sample sizes were based on power analysis calculations, which demonstrated that a 30% difference between 6 cases and controls will achieve a power of 80%.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn cultured rat embryonic fibroblasts and in the adult rat liver, metabolic stress induced by caloric restriction increases Suv39h1, the mammalian homolog of Su(var)3-9.
“In cultured rat embryonic fibroblasts and in the adult rat liver, metabolic stress induced by caloric restriction increases Suv39h1, the mammalian homolog of Su(var)3-945.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [45] Bosch-Presegué, L. et al. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol. Cell 42, 210–223 (2011). source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningHeterochromatin loss likely permits increased expression of non-protein coding RNA transcripts.
“heterochromatin loss likely permits increased expression of non-protein coding RNA transcripts”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataRT-PCR confirmed RNAi-mediated knockdown of Su(var)205 and Su(var)3-9.
“We used RT-PCR to confirm RNAi-mediated knockdown of Su(var)205 and Su(var)3-9 (Supplementary Fig. 2a).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataDNA-damage induced heterochromatin loss causes a global shift in gene expression towards a more developmental state that results from neuronal dedifferentiation, triggering inappropriate cell cycle reentry and subsequent apoptosis.
“Our data suggest that DNA-damage induced heterochromatin loss causes a global shift in gene expression towards a more developmental state that results from neuronal dedifferentiation, triggering inappropriate cell cycle reentry and subsequent apoptosis”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenData collection and analysis were not routinely performed blind to the conditions of the experiments.
“Data collection and analysis were not routinely performed blind to the conditions of the experiments.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenJNPL3 mice are used in compliance with ethical guidelines and regulations.
“JNPL3 mice are housed 2-5 per cage in a vivarium with a 12 hour off/on light/dark cycle and are used compliance with ethical guidelines and regulations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Study design and conductnone givenThe Wilcoxon rank-sum test is the most appropriate to use when the underlying distribution is unknown and the sample size is small.
“This non-parametric test is the most appropriate to use when the underlying distribution is unknown and the sample size is small.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenHuman control and AD brains with a postmortem interval of less than 24 hours were collected through the autopsy service at Brigham and Women's Hospital under the appropriate IRB.
“human control and AD brains with a postmortem interval of less than 24 hours were collected through the autopsy service at Brigham and Women’s Hospital under the appropriate IRB.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
Study design and conductreasoningThe input is minimally informative about the normalized ChIP.
“This procedure ensures that the input is minimally informative about the normalized ChIP.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoningWe tested for independence between both expression and chromatin states with a large sample size, and thus fulfilled the criteria for this non-parametric test.
“We tested for independence between both expression and chromatin states with a large sample size, and thus fulfilled the criteria for this non-parametric test.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The human AD postmortem brain samples and controls are representative of AD and non-demented controls, respectively, and differ only in AD-related pathology.
“We next used quantitative methods to validate the loss of H3K9me2 and increase of PIWIL1 levels in AD in age-, gender-, and postmortem interval-matched cases and controls.”
The paper relies on this without support.
The fetal brain gene expression profile is a valid reference for a dedifferentiated state.
“We compared gene expression profiles of fetal brains, human control hippocampal neurons, hippocampal neurons from AD, and whole hippocampal tissue from control and three stages of AD.”
The paper relies on this without support.
Ago3 is homologous to the human gene PIWIL1.
“Ago3 is homologous to the human gene PIWIL1”
The paper relies on this without support.
CG15661 is homologous to the human gene UGT1A10.
“CG15661 is homologous to the human gene UGT1A10.”
The paper relies on this without support.
Variance is similar between groups that are being compared.
“Variance is similar between groups that are being compared.”
The authors state this as an assumption.
Data distribution is normal (except for ChIP-seq analysis).
“Data distribution was assumed to be normal but this was not formally tested except for ChIP-seq analysis.”
The paper relies on this without support.
The simple external exoskeleton structure of the fly results in head preparations composed of primarily nervous system tissue.
“the simple external exoskeleton structure of the fly results in head preparations composed of primarily nervous system tissue.”
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?
Drosophila 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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
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 measuredExpression 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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
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 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 Frost et al. 2014
The Results section on chromatin structure reports reduced heterochromatin markers and diffuse chromocenter labeling in tau-transgenic Drosophila, supporting tau-associated heterochromatin decondensation. The paper does not establish damage to the lamin nucleoskeleton as its cause; the Discussion instead identifies oxidative stress and DNA damage as one mechanism. The retrotransposon claim is attached to other citations, not Frost et al. (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 [137]
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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
Loss-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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
Neuronal 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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
Sample 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.”
From Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies (2018) · cites this paper as [10]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1038/nature01126
InfoThe cited work was retracted on 2015-05-07 (notice 10.1038/nature14421), not before this paper was published (2014-01-26).
Cited work 10.1038/nature01126 · retracted 2015-05-07 · notice 10.1038/nature14421 · this paper published 2014-01-26
“Ash1 is a histone methyltransferase that promotes euchromatin formation and transcriptional activation by methylating histones such as H3K4 and H3K36 22 .”
Cites
1 retracted
Histone methylation by the Drosophila epigenetic transcriptional regulator Ash1
Beisel, C., Imhof, A., Greene, J., Kremmer, E., & Sauer, F. (2002) · Nature · doi:10.1038/nature01126 · Cited by 310 · cited 2× · see citing works
“Ash1 is a histone methyltransferase that promotes euchromatin formation and transcriptional activation by methylating histones such as H3K4 and H3K36 22 .”
RetractedUltrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849 · see citing works
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“Ago3 regulates PIWI-associated RNAs (piRNAs) 32 , a highly conserved class of small RNAs that are required for post-transcriptional gene silencing of transposons 33,34 .”
ChromHMM: automating chromatin-state discovery and characterization
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“A major pathological feature of AD and other tauopathies is the accumulation of abnormally phosphorylated forms of tau in the brains of affected individuals 1 .”
The NIH Roadmap Epigenomics Mapping Consortium
Bernstein, B. E., Stamatoyannopoulos, J. A., Costello, J. F., Ren, B., Milosavljevic, A., Meissner, A., Kellis, M., Marra, M. A., Beaudet, A. L., Ecker, J. R., et al. (2010) · Nature Biotechnology · doi:10.1038/nbt1010-1045 · Cited by 1,892 · cited 1× · see citing works
“In order to classify genes as heterochromatic or euchromatic, we utilized ChIP-seq data sets for all six publicly available histone modifications in the human hippocampus: H3K4me1, H3K4me3, H3K36me3, H3K9me3, H3K27me3, and H3K9ac (NIH Epigenomics Roadmap Project 37 ).”
A germline-specific class of small RNAs binds mammalian Piwi proteins
Girard, A., Sachidanandam, R., Hannon, G. J., & Carmell, M. A. (2006) · Nature · doi:10.1038/nature04917 · Cited by 1,762 · cited 2× · see citing works
“Ago3 regulates PIWI-interacting RNAs, or piRNAs, a large class of highly conserved small noncoding RNAs that are responsible for silencing transposons 33,34 .”
g:Profiler—a web-based toolset for functional profiling of gene lists from large-scale experiments
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A novel class of small RNAs bind to MILI protein in mouse testes
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Tau is a candidate gene for chromosome 17 frontotemporal dementia
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“Flies were collected in fresh vials on the day of eclosion and were transferred without anesthesia to fresh vials on days 3, 5, 7, and 9.”
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Propagation of Tau Misfolding from the Outside to the Inside of a Cell
Frost, B., Jacks, R. L., & Diamond, M. I. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m808759200 · Cited by 1,252 · see citing works
Self-citationBlalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., & Landfield, P. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308512100 · Cited by 1,025 · see citing works
Tauopathy in <i>Drosophila</i> : Neurodegeneration Without Neurofibrillary Tangles
Wittmann, C. W., Wszolek, M. F., Shulman, J. M., Salvaterra, P. M., Lewis, J., Hutton, M., & Feany, M. B. (2001) · Science · doi:10.1126/science.1062382 · Cited by 939 · cited 3× · see citing works
“Pan-neuronal transgenic expression of an FTDP-17 mutant form of human tau, tau R406W , in Drosophila causes progressive neurodegeneration and provides a well-characterized in vivo genetic model of tau neurotoxicity 7,15,16 .”
Self-citationUnlocking the secrets of the genome
Celniker, S., Dillon, L. A. L., Gerstein, M., Gunsalus, K. C., Henikoff, S., Karpen, G. H., Kellis, M., Lai, E. C., Lieb, J. D., MacAlpine, D. M., et al. (2009) · Nature · doi:10.1038/459927a · Cited by 767 · cited 3× · see citing works
“These five genes are classified as moderately to highly expressed (modEncode Project 31 ) in Drosophila heads despite their heterochromatic environment, while the six genes with increased expression in tau transgenic Drosophila are classified as heterochromatically silenced, with no to low baseline…”
Purification and properties of an ATP-dependent nucleosome remodeling factor
Tsukiyama, T., & Wu, C. C. M. (1995) · Cell · doi:10.1016/0092-8674(95)90216-3 · Cited by 616 · cited 1× · see citing works
“The nucleosome remodeling factor (NURF) complex catalyzes ATP-dependent nucleosome sliding and is required for transcriptional activation 23 .”
Genome-wide analysis of Polycomb targets in Drosophila melanogaster
Schwartz, Y. B., Kahn, T. G., Nix, D. A., Li, X., Bourgon, R., Biggin, M. D., & Pirrotta, V. (2006) · Nature Genetics · doi:10.1038/ng1817 · Cited by 610 · see citing works
Genome-wide chromatin state transitions associated with developmental and environmental cues
Zhu, J., Adli, M., Zou, J., Verstappen, G., Coyne, M. J., Zhang, X.-L., Durham, T. J., Miri, M., Deshpande, V., Jager, P. D., et al. (2013) · Cell · doi:10.1016/j.cell.2012.12.033 · Cited by 553 · see citing works
Hutchinson, E. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn2985 · Cited by 534 · see citing works
Hensley, K., Maidt, M. L., Yu, Z., Sang, H., Markesbery, W. R., & Floyd, R. A. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-20-08126.1998 · Cited by 508 · see citing works
Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo
Fulga, T. A., Elson-Schwab, I., Khurana, V., Steinhilb, M. L., Spires, T. L., Hyman, B. T., & Feany, M. B. (2007) · Nature Cell Biology · doi:10.1038/ncb1528 · Cited by 452 · see citing works
Self-citationTau Promotes Neurodegeneration via DRP1 Mislocalization In Vivo
DuBoff, B., Götz, J., & Feany, M. B. (2012) · Neuron · doi:10.1016/j.neuron.2012.06.026 · Cited by 377 · cited 1× · see citing works
“Pathologic tau causes an increase in actin stabilization 18 that inhibits association of the fission protein Drp1 with mitochondria, leading to mitochondrial elongation and the production of reactive oxygen species 44 .”
Self-citationJuliano, C., Wang, J., & Lin, H. (2011) · Annual Review of Genetics · doi:10.1146/annurev-genet-110410-132541 · Cited by 374 · see citing works
Local caspase activity directs engulfment of dendrites during pruning
Williams, D. W., Kondo, S., Krzyzanowska, A., Hiromi, Y., & Truman, J. W. (2006) · Nature Neuroscience · doi:10.1038/nn1774 · Cited by 369 · see citing works
Cell Cycle Activation Linked to Neuronal Cell Death Initiated by DNA Damage
Kruman, I. I., Wersto, R. P., Cardozo‐Pelaez, F., Smilenov, L. B., Chan, S. L., Chrest, F. J., Emokpae, R., Gorospe, M., & Mattson, M. P. (2004) · Neuron · doi:10.1016/s0896-6273(04)00017-0 · Cited by 365 · cited 1× · see citing works
“Although multiple lines of evidence implicate oxidative DNA damage and aberrant neuronal cell cycle activation in the toxic cascade triggered in tauopathies 6-8 , the mechanisms controlling the interplay between these processes in terminally differentiated neurons are unknown.”
Oxidative stress mediates tau-induced neurodegeneration in Drosophila
Dias-Santagata, D., Fulga, T. A., Duttaroy, A., & Feany, M. B. (2007) · Journal of Clinical Investigation · doi:10.1172/jci28769 · Cited by 318 · see citing works
Self-citationTau Pathology in Two Dutch Families with Mutations in the Microtubule-Binding Region of Tau
Spillantini, M. G., Crowther, R. A., Kamphorst, W., Heutink, P., & Swieten, J. C. V. (1998) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65721-5 · Cited by 293 · cited 2× · see citing works
“chromosome 17 (FTDP-17), confirms tau as a causal factor in neurodegenerative disease pathogenesis 2-4 .”
TOR-Mediated Cell-Cycle Activation Causes Neurodegeneration in a Drosophila Tauopathy Model
Khurana, V., Lu, Y., Steinhilb, M. L., Oldham, S., Shulman, J. M., & Feany, M. B. (2006) · Current Biology · doi:10.1016/j.cub.2005.12.042 · Cited by 266 · cited 8× · see citing works
“Because cell cycle activation in postmitotic neurons causes apoptosis in Drosophila 7 , these data also indicate that heterochromatin loss is not a result of general cellular toxicity.”
InfluentialSelf-citationp53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage
Rubbi, C. P., & Milner, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg082 · Cited by 229 · cited 1× · see citing works
“Since DNA damage can cause widespread heterochromatin loss 28,29 , and reduced Trxr-1 or Sod2 function causes DNA damage, we asked if loss of Trxr-1 or Sod2 function causes heterochromatin relaxation.”
FlyBase: improvements to the bibliography
Marygold, S. J., Leyland, P. C., Seal, R. L., Goodman, J. L., Thurmond, J., Strelets, V. B., & Wilson, R. J. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1024 · Cited by 227 · see citing works
Gene expression profiling in human neurodegenerative disease
Cooper‐Knock, J., Kirby, J., Ferraiuolo, L., Heath, P. R., Rattray, M., & Shaw, P. J. (2012) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.156 · Cited by 218 · cited 1× · see citing works
“Given that gene expression signatures in neurodegenerative diseases can be conserved from brain to peripheral tissues 41 , we next compared expression levels of heterochromatic and euchromatic genes between control and AD peripheral blood mononuclear cells (Supplementary Fig.”
Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients
Mullaart, E., Boerrigter, M. E. T. I., Ravid, R., Swaab, D. F., & Vijg, J. (1990) · Neurobiology of Aging · doi:10.1016/0197-4580(90)90542-8 · Cited by 201 · cited 1× · see citing works
“Oxidative DNA damage and activation of the cell cycle are known to promote chromatin remodeling 11,12 , are present in human AD brains 24,25 , and are critical components of tau-induced neurodegeneration in our Drosophila model of tauopathy 7,8,16 .”
The functional organisation of glia in the adult brain of Drosophila and other insects
Edwards, T. N., & Meinertzhagen, I. A. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.01.001 · Cited by 200 · cited 1× · see citing works
“Neurons outnumber glia ten to one in Drosophila 36 .”
Isolation of neuronal chromatin from brain tissue
Jiang, Y., Matevossian, A., Huang, H.-S., Straubhaar, J., & Akbarian, S. (2008) · BMC Neuroscience · doi:10.1186/1471-2202-9-42 · Cited by 193 · cited 1× · see citing works
“Nuclei were extracted and labeled with NeuN as described previously 55 .”
Tau Phosphorylation Sites Work in Concert to Promote Neurotoxicity In Vivo
Steinhilb, M. L., Dias-Santagata, D., Fulga, T. A., Felch, D. L., & Feany, M. B. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-04-0327 · Cited by 187 · cited 1× · see citing works
“chromosome 17 (FTDP-17), confirms tau as a causal factor in neurodegenerative disease pathogenesis 2-4 .”
Self-citationHeterochromatic Genome Stability Requires Regulators of Histone H3 K9 Methylation
Peng, J. C., & Karpen, G. H. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000435 · Cited by 183 · cited 1× · see citing works
“An appropriate balance and distribution of active and repressed chromatin is required for proper transcriptional control, maintaining nuclear architecture and genomic stability 13 , and regulating the cell cycle 14 .”
Transcriptional profiling of Alzheimer blood mononuclear cells by microarray
Maes, O. C., Xu, S., Yu, B., Chertkow, H. M., Wang, E., & Schipper, H. M. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.08.004 · Cited by 182 · see citing works
Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization
Sjöberg, M. K., Shestakova, E., Mansuroglu, Z., Maccioni, R. B., & Bonnefoy, E. (2006) · Journal of Cell Science · doi:10.1242/jcs.02907 · Cited by 166 · see citing works
Ribosomal DNA contributes to global chromatin regulation
Paredes, S., & Maggert, K. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906811106 · Cited by 156 · see citing works
Heterochromatin structure and function
Dillon, N. (2004) · Biology of the Cell · doi:10.1016/j.biolcel.2004.06.003 · Cited by 153 · cited 4× · see citing works
“Oxidative DNA damage and activation of the cell cycle are known to promote chromatin remodeling 11,12 , are present in human AD brains 24,25 , and are critical components of tau-induced neurodegeneration in our Drosophila model of tauopathy 7,8,16 .”
InfluentialAlzheimer Disease in 2020Preprint
Holtzman, D. M., Mandelkow, E., & Selkoe, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011585 · Cited by 151 · cited 2× · see citing works
“Flies were collected in fresh vials on the day of eclosion and were transferred without anesthesia to fresh vials on days 3, 5, 7, and 9.”
Drosophila MSL complex globally acetylates H4K16 on the male X chromosome for dosage compensation
Gelbart, M. E., Larschan, E., Peng, S., Park, P. J., & Kuroda, M. I. (2009) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1644 · Cited by 143 · see citing works
Bosch-Presegué, L., Raurell-Vila, H., Marazuela-Duque, A., Kane-Goldsmith, N., Valle, A., Oliver, J., Serrano, L., & Vaquero, A. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.034 · Cited by 138 · see citing works
Wei, Y., Qu, M.-H., Wang, X.-S., Chen, L., Wang, D.-L., Liu, Y., Hua, Q., & He, R.-Q. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002600 · Cited by 129 · cited 1× · see citing works
“In vitro and in cultured cells, tau binds the minor groove of the DNA double helix and is thought to protect DNA from oxidative damage 46-48 .”
Ambegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · cited 1× · see citing works
“Based on recovery of chromatin regulators in unbiased forward genetic screens for modifiers of tau neurotoxicity 9,10 (M.B.F., unpublished data), and because chromatin remodeling is associated with oxidative DNA damage and cell cycle regulation 11,12 , we hypothesized that oxidative stress-induced…”
Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila
Blard, O., Feuillette, S., Bou, J., Chaumette, B., Frébourg, T., Campion, D., & Lecourtois, M. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm011 · Cited by 110 · cited 4× · see citing works
“Flies were collected in fresh vials on the day of eclosion and were transferred without anesthesia to fresh vials on days 3, 5, 7, and 9.”
InfluentialKrylova, S. M., Musheev, M., Nutiu, R., Li, Y., Lee, G., & Krylov, S. N. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.01.032 · Cited by 96 · cited 1× · see citing works
“In vitro and in cultured cells, tau binds the minor groove of the DNA double helix and is thought to protect DNA from oxidative damage 46-48 .”
Clusters of Conserved Beta Cell Marker Genes for Assessment of Beta Cell Phenotype
Martens, G. A., Jiang, L., Hellemans, K., Stangé, G. M., Heimberg, H., Nielsen, F. C., Sand, O., van Helden, J., Gorus, F., & PIPELEERS, D. G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024134 · Cited by 93 · cited 1× · see citing works
“Using microarray data sets from hippocampal neurons from control and AD brain, whole hippocampi of control brains and brains with different stages of AD (GSE1297 39 ), and whole fetal brain (GSE30803 59 ), we defined heterochromatic genes as described above.”
Developmental regulation of heterochromatin-mediated gene silencing in <i>Drosophila</i>
Lu, B. Y., Ma, J., & Eissenberg, J. C. (1998) · Development · doi:10.1242/dev.125.12.2223 · Cited by 88 · see citing works
Missirlis, F., Hirosawa, M., Grönke, S., Schäfer, U., Jäckle, H., Ulschmid, J. K., Becker, K., & Phillips, J. P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111692200 · Cited by 86 · see citing works
HP1 modulates the transcription of cell-cycle regulators in Drosophila melanogaster
Lucia, F. D., Ni, J., Vaillant, C., & Sun, F.-L. (2005) · Nucleic Acids Research · doi:10.1093/nar/gki584 · Cited by 80 · cited 1× · see citing works
“An appropriate balance and distribution of active and repressed chromatin is required for proper transcriptional control, maintaining nuclear architecture and genomic stability 13 , and regulating the cell cycle 14 .”
Selection of Candidate Housekeeping Genes for Normalization in Human Postmortem Brain Samples
Penna, I., Vella, S., Gigoni, A., Russo, C., Cancedda, R., & Pagano, A. (2011) · International Journal of Molecular Sciences · doi:10.3390/ijms12095461 · Cited by 79 · cited 1× · see citing works
“EIFA4 and CYC1 were selected as internal controls for human RT-PCR based upon their stability in postmortem brain of AD patients 54 .”
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 56 · cited 4× · see citing works
“Oxidative DNA damage and activation of the cell cycle are known to promote chromatin remodeling 11,12 , are present in human AD brains 24,25 , and are critical components of tau-induced neurodegeneration in our Drosophila model of tauopathy 7,8,16 .”
InfluentialSelf-citationChromatin Proteins: Key Responders to Stress
Smith, K. T., & Workman, J. L. (2012) · PLoS Biology · doi:10.1371/journal.pbio.1001371 · Cited by 36 · see citing works
Berzsenyi, M. D., Woollard, D. J., McLean, C., et al. (2011) · Journal of Hepatology · doi:10.1016/j.jhep.2010.12.021 · Cited by 26 · see citing works
Hittelman, W. N., & Pollard, M. (1984) · Carcinogenesis · doi:10.1093/carcin/5.10.1277 · Cited by 25 · see citing works
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Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Chromatin-state discovery and genome annotation with ChromHMM
Ernst, J., & Kellis, M. (2017) · Nature Protocols · doi:10.1038/nprot.2017.124 · Cited by 918 · see citing works
“ChromHMM has had applications to studying diseases such as Alzheimer’s disease 28,29 , neurodegeneration 30 , type 2 diabetes 31 , and cancer 32–35 , among many other diseases.”
Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · see citing works
The road to restoring neural circuits for the treatment of Alzheimer's disease
Canter, R. G., Penney, J., & Tsai, L.-H. (2016) · Nature · doi:10.1038/nature20412 · Cited by 565 · see citing works
Tau association with synaptic vesicles causes presynaptic dysfunction
Zhou, L., McInnes, J., Wierda, K., Holt, M., Herrmann, A. G., Jackson, R. J., Wang, Y.-C., Swerts, J., Beyens, J., Miskiewicz, K., et al. (2017) · Nature Communications · doi:10.1038/ncomms15295 · Cited by 434 · see citing works
Repression of the Antioxidant NRF2 Pathway in Premature Aging
Kubben, N., Zhang, W., Wang, L., Voss, T. C., Yang, J., Qu, J., Liu, G.-H., & Misteli, T. (2016) · Cell · doi:10.1016/j.cell.2016.05.017 · Cited by 489 · see citing works
“Subsequently, increased ROS levels can cause a severe loss of heterochromatin (Frost et al., 2014), which precedes and by itself is sufficient to activate DNA damage signaling as observed in progerin-inducible fibroblasts (Pegoraro et al., 2009).”
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
Epigenetic Regulation in Neurodegenerative Diseases
Berson, A., Nativio, R., Berger, S. L., & Bonini, N. M. (2018) · Trends in Neurosciences · doi:10.1016/j.tins.2018.05.005 · Cited by 386 · see citing works
Nativio, R., Lan, Y., Donahue, G., Sidoli, S., Berson, A., Srinivasan, A. R., Shcherbakova, O., Amlie-Wolf, A., Nie, J., Cui, X., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0696-0 · Cited by 380 · see citing works
Amyloid-β and tau complexity — towards improved biomarkers and targeted therapies
Polanco, J. C., Li, C., Bodea, L., Martínez‐Mármol, R., Meunier, F. A., & Götz, J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.162 · Cited by 374 · see citing works
Ferreira, S. T., Lourenco, M. V., Oliveira, M. M., & De Felice, F. G. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00191 · Cited by 373 · see citing works
“…pathology has further been shown to cause brain oxidative and ER stress in animal models of AD (DiasSantagata et al., 2007; Abisambra et al., 2013; Frost et al., 2014) and, of clinical relevance, Aβ-linked cortical volume loss only develops in the presence of p-tau, further connecting amyloid to…”
BackgroundShared molecular and cellular mechanisms of premature ageing and ageing-associated diseases
Kubben, N., & Misteli, T. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.68 · Cited by 320 · see citing works
Tau Activates Transposable Elements in Alzheimer’s Disease
Guo, C., Jeong, H.-H., Hsieh, Y.-C., Klein, H.-U., Bennett, D. A., De Jager, P. L., Liu, Z., & Shulman, J. M. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.004 · Cited by 315 · see citing works
“As introduced above, Tau pathology is associated with global chromatin reorganization and dysregulated gene expression (Frost et al., 2014; Klein et al., 2018).”
BackgroundInfluentialSun, W., Samimi, H., Gamez, M., Zare, H., & Frost, B. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0194-1 · Cited by 315 · see citing works
Self-citationThe role of histone modifications: from neurodevelopment to neurodiseases
Park, J., Lee, K., Kim, K., & Yi, S.-J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01078-9 · Cited by 321 · see citing works
“5).162 Histone acetyltransferase activity of CBP (KAT3A) is required for neurogenesis and memory consolidation in rodents.163–167 Several studies suggested that an increase in CBP expression is considered a valid therapeutic approach for AD.”
BackgroundInfluentialA walk through tau therapeutic strategies
Jadhav, S., Ávila, J., Schöll, M., Kovács, G. G., Kövari, E., Škrabana, R., Evans, L., Kontseková, E., Malawska, B., de Silva, R., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0664-z · Cited by 286 · see citing works
Tau-based therapies in neurodegeneration: opportunities and challenges
Li, C., & Götz, J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.155 · Cited by 272 · see citing works
Molecular Pathogenesis of the Tauopathies
Götz, J., Halliday, G., & Nisbet, R. M. (2019) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-012418-012936 · Cited by 276 · see citing works
Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability
Alonso, A. D., Cohen, L. S., Corbo, C., Morozova, V., ElIdrissi, A., Phillips, G., & Kleiman, F. E. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00338 · Cited by 278 · see citing works
“Though the majority of evidence thus far supports the relationship of tau toxicity with disruption of the microtubule system, emerging evidence suggest that tau biological functions are not restricted to the cytoskeletal system: tau is present in the nuclei (Brady et al., 1995; Greenwood and Johnson, 1995; Frost et al…”
BackgroundKlein, H., Aubin, C., Gjoneska, E., Sullivan, S. E., Kaskow, B. J., Tang, A. Y., Smith, R. V., Xu, J., Pfenning, A. R., Bernstein, B., et al. (2018) · Nature Neuroscience · doi:10.1038/s41593-018-0291-1 · Cited by 267 · see citing works
“Previous work in Drosophila suggested that the lamin nucleoskeleton is disrupted in tauopathies, which causes heterochromatin relaxation and mediates neuronal cell death 7,8 .”
Regulation of Stem Cell Aging by Metabolism and Epigenetics
Ren, R., Ocampo, A., Liu, G., & Belmonte, J. C. I. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.019 · Cited by 269 · see citing works
Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer’s disease
Otero-Garcia, M., Mahajani, S. U., Wakhloo, D., Tang, W., Xue, Y.-Q., Morabito, S., Pan, J., Oberhauser, J., Madira, A. E., Shakouri, T., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.06.021 · Cited by 262 · see citing works
Date Palm Tree (Phoenix dactylifera L.): Natural Products and Therapeutic Options
Al-Alawi, R. A., Al-Mashiqri, J. H., Al-Nadabi, J. S. M., Al-Shihi, B. I., & Baqi, Y. (2017) · Frontiers in Plant Science · doi:10.3389/fpls.2017.00845 · Cited by 336 · see citing works
“Antioxidants have received great attention because they act as free radicals scavenger related to various diseases including cancer (Gorrini et al., 2013), heart diseases (Moss and Ramji, 2016), Alzheimer’s (Frost et al., 2014), and Parkinson’s disease (Kim et al., 2015).”
BackgroundOxidative Stress Signaling to Chromatin in Health and Disease
Kreuz, S., & Fischle, W. (2016) · Epigenomics · doi:10.2217/epi-2016-0002 · Cited by 254 · see citing works
Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome
Hernández‐Ortega, K., Garcia‐Esparcia, P., Gil, L., Lucas, J. J., & Ferrer, I. (2016) · Brain Pathology · doi:10.1111/bpa.12335 · Cited by 245 · see citing works
“This is a very important point as it has been postulated that tau promotes neurodegeneration through global chromatin relaxation in AD because increased tau hyperphosphorylation and tangle formation in the cytoplasm parallels chromatin disassembly (39).”
BackgroundSynaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau
McInnes, J., Wierda, K., Snellinx, A., Bounti, L., Wang, Y.-C., Stancu, I.-C., Apóstolo, N., Gevaert, K., Dewachter, I., Spires-Jones, T. L., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.01.022 · Cited by 242 · see citing works
“Other notable studies could also rescue other Tau phenotypes by heterozygous loss of genetic modifiers (Frost et al., 2014; Lasagna-Reeves et al., 2016).”
Cellular and pathological functions of tau
Bravo, C. P., Naguib, S. A., & Gan, L. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00753-9 · Cited by 245 · see citing works
“…expressing pathogenic R406W tau displayed a decrease in nuclear tension 139 (which refers to the tension on the nuclear cytoskeleton), a decrease in nuclear calcium and CREB 140 , as well as chromatin relaxation, which promoted neurodegeneration by resulting in aberrant gene expression 141 .”
A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies
Orr, M. E., Sullivan, A. C., & Frost, B. E. (2017) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.03.011 · Cited by 232 · see citing works
“Pathogenic tau-induced oxidative stress and lamin depletion cause constitutive heterochromatin to relax, which allows genes that are normally silenced by constitutive heterochromatin to be transcribed [101,102].”
BackgroundResultSelf-citationLoss 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
“In the context of neurodegeneration, tau protein, which forms neurofibrillary tangles in Alzheimer’s disease, alters heterochromatin organization, increases DNA breaks, and increases transcription of heterochromatic regions (Frost et al., 2014; Man-suroglu et al., 2016).”
BackgroundLamin Dysfunction Mediates Neurodegeneration in Tauopathies
Frost, B., Bardai, F. H., & Feany, M. B. (2016) · Current Biology · doi:10.1016/j.cub.2015.11.039 · Cited by 226 · see citing works
“Like pathological tau [4], Lamin dysfunction significantly reduced total levels of dimethylated lysine 9 of histone 3 (H3K9me2) and heterochromatin protein 1a (HP1a), markers of heterochromatic DNA, in adult Drosophila brains (Figure 2A).”
InfluentialSelf-citationα-synuclein Induces Mitochondrial Dysfunction through Spectrin and the Actin Cytoskeleton
Ordonez, D. G., Lee, M. K., & Feany, M. B. (2018) · Neuron · doi:10.1016/j.neuron.2017.11.036 · Cited by 227 · see citing works
Self-citationTau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
“Furthermore, dysregulated gene expression and rRNA synthesis occur resulting in the rise of altered protein synthesis [547,548].”
BackgroundREST and neural gene network dysregulation in iPSC models of Alzheimer’s disease
Meyer, K., Feldman, H. M., Lu, T., Drake, D., Lim, E. T., Ling, K.-H., Bishop, N. A., Pan, Y., Seo, J., Lin, Y.-T., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.01.023 · Cited by 216 · see citing works
“These changes in nuclear membrane structure and changes in chromatin were associated with increased activity of the tau kinase CDK5 and abnormal tau phosphorylation (Chang et al., 2011; Frost et al., 2014).”
BackgroundLiu, Z., Li, T., Li, P., Wei, N., Zhao, Z., Liang, H., Ji, X., Chen, W., Xue, M., & Wei, J. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/352723 · Cited by 208 · see citing works
“[104] B.”
Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer’s disease mice
Bustos, F. J., Ampuero, E., Jury, N., Aguilar, R., Falahi, F., Toledo, J. A., Ahumada, J., Lata, J., Cubillos, P., Henríquez, B., et al. (2017) · Brain · doi:10.1093/brain/awx272 · Cited by 205 · see citing works
“While epigenetic dysregulation is implicated in several neurodevelopmental, neuropsychiatric and neurodegenerative disorders, including Alzheimer’s and Huntington’s diseases (Gräff et al., 2011; Dekker et al., 2014; Frost et al., 2014), it is challenging to directly associate epigenetic (dys)regulation with specific n…”
BackgroundAxonal Degeneration during Aging and Its Functional Role in Neurodegenerative Disorders
Salvadores, N., Sanhueza, M., Manque, P., & Court, F. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00451 · Cited by 182 · see citing works
“…protein tau, a main player in AD pathomechanism, triggers heterochromatin relaxation in Frontiers in Neuroscience | www.frontiersin.org 6 September 2017 | Volume 11 | Article 451 transgenic flies and AD patients in a mechanism mediated by oxidative stress and DNA damage (Frost et al., 2014).”
BackgroundEpigenetics of Alzheimer’s Disease
Perković, M. N., Paska, A. V., Konjevod, M., Kouter, K., Štrac, D. Š., Erjavec, G. N., & Pivac, N. (2021) · Biomolecules · doi:10.3390/biom11020195 · Cited by 181 · see citing works
“Oxidative stress and subsequent DNA damage have been identified as a mechanistic link between transgenic tau expression and heterochromatin relaxation [117].”
BackgroundInhibition of EHMT1/2 rescues synaptic and cognitive functions for Alzheimer’s disease
Zheng, Y., Liu, A., Wang, Z.-J., Cao, Q., Wang, W., Lin, L., Ma, K., Zhang, F., Wei, J., Matas, E., et al. (2019) · Brain · doi:10.1093/brain/awy354 · Cited by 168 · see citing works
“On the other hand, loss of heterochromatin and increased gene expression has also been reported in Alzheimer’s disease conditions (Frost et al., 2014).”
BackgroundEpigenetic Alterations in Alzheimer’s Disease
Sanchez-Mut, J. V., & Gräff, J. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00347 · Cited by 168 · see citing works
“…contradictory results: decreased heterochromatin compaction associated with lower H3K9me2 levels in a TAU Drosophila AD model and human samples (Frost et al., 2014), no significant differences in the heterochromatin of p25/cdk5 Ad mouse model measured by H3K9me3 (Gjoneska et al., 2015), and…”
ResultSIRT3 consolidates heterochromatin and counteracts senescence
Diao, Z., Ji, Q., Wu, Z., Zhang, W., Cai, Y., Wang, Z., Hu, J., Liu, Z., Wang, Q., Bi, S., et al. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab161 · Cited by 171 · see citing works
“Mitochondrial ROS may not only affect DNA and histone modifications via the modulation of epigenetic modifiers (84,85), but also lead to heterochromatin loss (86).”
BackgroundNuclear Tau and Its Potential Role in Alzheimer’s Disease
Bukar Maina, M., Al-Hilaly, Y., & Serpell, L. (2016) · Biomolecules · doi:10.3390/biom6010009 · Cited by 161 · see citing works
“Tau phosphorylation has been suggested to be an important modifier of its function and the induction of toxicity in neurons [43,65].”
BackgroundInfluentialExperimental evidence for the age dependence of tau protein spread in the brain
Wegmann, S., Bennett, R. E., Delorme, L., Robbins, A. B., Hu, M., MacKenzie, D., Kirk, M. J., Schiantarelli, J., Tunio, N., Amaral, A. C., et al. (2019) · Science Advances · doi:10.1126/sciadv.aaw6404 · Cited by 144 · see citing works
Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns
Sanchez-Mut, J. V., Heyn, H., Vidal, E., Morán, S., Sayols, S., Delgado‐Morales, R., Schultz, M. D., Ansoleaga, B., Garcia‐Esparcia, P., Pons‐Espinal, M., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2015.214 · Cited by 157 · see citing works
Basheer, N., Smolek, T., Hassan, I., Liu, F., Iqbal, K., Zilka, N., & Novak, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02113-z · Cited by 159 · 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
Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies
Forrest, S. L., Kril, J. J., Stevens, C. H., Kwok, J. B., Hallupp, M., Kim, W. S., Huang, Y. M., McGinley, C. V., Werka, H., Kiernan, M. C., et al. (2017) · Brain · doi:10.1093/brain/awx328 · Cited by 148 · see citing works
“nuclear and dendritic functions (Frost et al., 2014; Ittner et al., 2016)], new insights into variations in pathogenesis are likely to be revealed.”
BackgroundMansuroglu, Z., Benhelli-Mokrani, H., Marcato, V., Sultan, A., Violet, M., Chauderlier, A., Delattre, L., Loyens, A., Talahari, S., Bégard, S., et al. (2016) · Scientific Reports · doi:10.1038/srep33047 · Cited by 146 · see citing works
Diverse Epigenetic Mechanisms of Human Disease
Brookes, E., & Shi, Y. (2014) · Annual Review of Genetics · doi:10.1146/annurev-genet-120213-092518 · Cited by 142 · see citing works
Current and emerging avenues for Alzheimer's disease drug targets
Loera‐Valencia, R., Cedazo-Mı́nguez, Á., Kenigsberg, P.-A., Page, G., Duarte, A. I., Giusti, P., Zusso, M., Robert, P. H., Frisoni, G. B., Cattaneo, A., et al. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12959 · Cited by 139 · see citing works
Increased acetyl and total histone levels in post-mortem Alzheimer's disease brain
Narayan, P. J., Lill, C. L., Faull, R. L. M., Curtis, M. A., & Dragunow, M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.11.023 · Cited by 133 · see citing works
Niewiadomska, G., Niewiadomski, W., Steczkowska, M., & Gąsiorowska, A. (2021) · Life · doi:10.3390/life11010028 · Cited by 132 · see citing works
“[50] suggested that changes in the structure of PCH, such as the disturbed localization pattern of H3K9me3, are partially responsible for the increased expression of heterochromatically silenced genes reported in the hippocampal neurons of AD patients [49].”
BackgroundP53 aggregation, interactions with tau, and impaired DNA damage response in Alzheimer’s disease
Farmer, K. M., Ghag, G., Puangmalai, N., Montalbano, M., Bhatt, N. N., & Kayed, R. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01012-6 · Cited by 126 · see citing works
“reported to cause heterochromatin relaxation while WT tau has been reported to protect DNA [35, 108].”
BackgroundGenome instability in Alzheimer disease
Hou, Y., Song, H., Croteau, D. L., Akbari, M., & Bohr, V. A. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2016.04.005 · Cited by 120 · see citing works
“Pathological tau has also been shown to affect global chromatin structure (Frost et al., 2014), probably via a mechanism involving lamin dysfunction (Frost et al.”
BackgroundConnecting the dots between tau dysfunction and neurodegeneration
Frost, B., Götz, J., & Feany, M. B. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.07.005 · Cited by 124 · see citing works
“Oxidative stress is a driver of heterochromatin loss in tauopathy, which has been recently identified as a novel mechanism of tau neurotoxicity as discussed below [68].”
BackgroundInfluentialSelf-citationDiversity of astroglial responses across human neurodegenerative disorders and brain aging
Ferrer, I. (2017) · Brain Pathology · doi:10.1111/bpa.12538 · Cited by 123 · see citing works
“Tau expression in astrocytes might putatively affect nuclear function and DNA transcription as postulated for tau-containing neurons in tauopathies and fly models (88, 136, 178, 213).”
BackgroundTau: The Center of a Signaling Nexus in Alzheimer's Disease
Khan, S. S., & Bloom, G. S. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00031 · 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
“While it remains unclear how relevant these results are for the human disease, it is noteworthy that human AD brains display alterations of heterochromatin, including a diffuse H3K9me2 staining and an altered distribution of heterochromatin protein 1 (HP1) [97].”
BackgroundDiseases of the nERVous system: retrotransposon activity in neurodegenerative disease
Tam, O. H., Ostrow, L. W., & Hammell, M. (2019) · Mobile DNA · doi:10.1186/s13100-019-0176-1 · Cited by 118 · see citing works
Tau Isoforms: Gaining Insight into MAPT Alternative Splicing
Corsi, A., Bombieri, C., Valenti, M. T., & Romanelli, M. G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315383 · Cited by 118 · see citing works
“Other works also indicate the involvement of Tau in genome stability [99] and in the regulation of heterochromatin integrity [100].”
BackgroundWu, Z., Qu, J., & Liu, G.-H. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00775-3 · Cited by 118 · see citing works
“…H3K9me3 and HP1 is associated with LINE-1 activation and β-amyloid deposition in physiologically aged brains of non-human primates 161 , and loss of heterochromatin is widespread in human tau transgenic Drosophila and mouse models, as well as in brains from individuals with Alzheimer disease 170 .”
Contributions of DNA Damage to Alzheimer’s Disease
Lin, X., Kapoor, A., Gu, Y., Chow, M. J., Peng, J., Zhao, K., & Tang, D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051666 · Cited by 117 · see citing works
Are there roles for brain cell senescence in aging and neurodegenerative disorders?
Tan, F. C. C., Hutchison, E. R., Eitan, E., & Mattson, M. P. (2014) · Biogerontology · doi:10.1007/s10522-014-9532-1 · Cited by 116 · see citing works
“A more recent study found that tau induces aberrant gene expression through ROS-mediated chromatin relaxation in both human AD patient tissue and in tau transgenic Drosophila and mice (Frost et al. 2014).”
Calderón‐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 114 · see citing works
Di, J., Cohen, L. S., Corbo, C. P., Phillips, G. R., Idrissi, A. E., & Alonso, A. D. C. (2016) · Scientific Reports · doi:10.1038/srep20833 · Cited by 112 · see citing works
Glial Tau Pathology in Tauopathies: Functional Consequences
Kahlson, M. A., & Colodner, K. J. (2015) · Journal of Experimental Neuroscience · doi:10.4137/jen.s25515 · Cited by 110 · see citing works
Bandrés‐Ciga, S., Sáez-Atiénzar, S., Kim, J., Makarious, M. B., Faghri, F., Díez-Fairén, M., Iwaki, H., Leonard, H. L., Botía, J. A., Ryten, M., et al. (2020) · Acta Neuropathologica · doi:10.1007/s00401-020-02181-3 · Cited by 109 · see citing works
Tau as a Biomarker of Neurodegeneration
Holper, S., Watson, R., & Yassi, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137307 · Cited by 114 · see citing works
“Nuclear tau also induces chromatin relaxation, with downstream implications for global transcription alterations [49].”
BackgroundThe involvement of tau in nucleolar transcription and the stress response
Maina, M. B., Bailey, L. J., Wagih, S., Biasetti, L., Pollack, S. J., Quinn, J. P., Thorpe, J. R., Doherty, A. J., & Serpell, L. C. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0565-6 · Cited by 109 · see citing works
Salminen, A., Haapasalo, A., Kauppinen, A., Kaarniranta, K., Soininen, H. S., & Hiltunen, M. O. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.05.001 · Cited by 105 · see citing works
Tau physiology and pathomechanisms in frontotemporal lobar degeneration
Bodea, L., Eckert, A., Ittner, L. M., Piguet, O., & Götz, J. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13600 · Cited by 104 · see citing works
“Tau-related chromatin relaxation was observed in a study encompassing human R406W tau Drosophila and JNPL3 mouse models of tauopathy, as well as AD brain samples (Frost et al. 2014).”
BackgroundMoving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer’s disease
Young‐Pearse, T. L., Lee, H., Hsieh, Y., Chou, V., & Selkoe, D. J. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.03.005 · Cited by 99 · see citing works
Nuclear pore complexes — a doorway to neural injury in neurodegeneration
Coyne, A. N., & Rothstein, J. D. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00653-6 · Cited by 96 · see citing works
Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases
Li, M., Burns, T. C., Morgan, A. A., & Khatri, P. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0093-y · Cited by 91 · see citing works
“The importance of chromatin regulation in neurodegenerative disease was recently highlighted in experiments showing that Tau-induced heterochromatin loss results in aberrant gene expression in tauopathies [104].”
BackgroundLifespan and Stress Resistance in Drosophila with Overexpressed DNA Repair Genes
Shaposhnikov, M., Proshkina, E., Shilova, L., Zhavoronkov, A., & Moskalev, A. (2015) · Scientific Reports · doi:10.1038/srep15299 · Cited by 88 · see citing works
Nuclear Dynamics of Heterochromatin Repair
Amaral, N., Ryu, T., Li, X., & Chiolo, I. (2017) · Trends in Genetics · doi:10.1016/j.tig.2016.12.004 · Cited by 91 · see citing works
Lee, M. Y., Lee, J.-H., Hyeon, S. J., Cho, H., Hwang, Y. J., Shin, J., McKee, A. C., Kowall, N. W., Kim, J., Stein, T. D., et al. (2020) · Aging Cell · doi:10.1111/acel.13153 · Cited by 89 · see citing works
“…is observed in structurally compact nuclei of neuronal cells while the heterochromatin relaxation or loss can be found in structurally disrupted nuclei of neuronal cells under degenerative stresses (Hajjar et al., 2019; Frost et al., 2014, 2016; El Town et al., 2012; Walker et al., 2013).”
BackgroundZhang, Y., Amaral, M. L., Zhu, C., Grieco, S. F., Hou, X., Lin, L., Buchanan, J., Tong, L., Preissl, S., Xu, X., et al. (2022) · Cell Research · doi:10.1038/s41422-022-00719-6 · Cited by 89 · see citing works
“Previous studies have suggested potential association of loss of heterochromatin and neurodegenerative disease.(69,70) Future studies are needed to examine the relationship between the heterochromatin loss in the excitatory neurons and cognitive declines.”
BackgroundVisser, P. J., Reus, L. M., Gobom, J., Jansen, I. E., Dicks, E., van der Lee, S. J., Tsolaki, M., Verhey, F. R. J., Popp, J., Martínez‐Lage, P., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00521-3 · Cited by 88 · see citing works
Centromere and Pericentromere Transcription: Roles and Regulation … in Sickness and in Health
Smurova, K., & Wulf, P. D. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00674 · Cited by 84 · see citing works
“Finally, the transcriptional de-repression of satellite sequences has been linked to tau-induced neurodegeneration, as in Alzheimer’s disease (Frost et al., 2014).”
BackgroundThe wide and growing range of lamin B-related diseases: from laminopathies to cancer
Evangelisti, C., Rusciano, I., Mongiorgi, S., Ramazzotti, G., Lattanzi, G., Manzoli, L., Cocco, L., & Ratti, S. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-04084-2 · Cited by 87 · see citing works
“Alzheimer’s Disease Neurodegeneration LMNB1 Decrease of expression Pathological tau decreases lamin B causing relaxation of constitutive heterochromatin that causes neuronal death [63]”
BackgroundRNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction
Montalbano, M., McAllen, S., Puangmalai, N., Sengupta, U., Bhatt, N. N., Johnson, O. D., Kharas, M. G., & Kayed, R. (2020) · Nature Communications · doi:10.1038/s41467-020-18022-6 · Cited by 86 · see citing works
TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling
Berson, A., Sartoris, A., Nativio, R., Deerlin, V. M. V., Toledo, J. B., Porta, S., Liu, S., Chung, C., Garcia, B. A., Lee, V. M. ‐., et al. (2017) · Current Biology · doi:10.1016/j.cub.2017.10.024 · Cited by 83 · see citing works
Patrick, E., Rajagopal, S., Wong, H.-K. A., McCabe, C., Xu, J., Tang, A., Imboywa, S. H., Schneider, J. A., Pochet, N., Krichevsky, A. M., et al. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0191-y · Cited by 77 · see citing works
“transcription, which is consistent with prior reports of epigenomic changes in certain model systems such as Drosophila Melanogaster DNA methylation profiles and the involvement of REST in AD [32, 33].”
ResultQi, H., Cantrelle, F., Benhelli‐Mokrani, H., Smet‐Nocca, C., Buée, L., Lippens, G. M., Bonnefoy, E., Galas, M., & Landrieu, I. (2015) · Biochemistry · doi:10.1021/bi5014613 · Cited by 83 · see citing works
Narne, P., Pandey, V., Simhadri, P. K., & Phanithi, P. B. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.11.007 · Cited by 80 · see citing works
Spatial genome organization and cognition
Rajarajan, P., Espeso‐Gil, S., Brennand, K., & Akbarian, S. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.124 · Cited by 80 · see citing works
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-citationA Primer on Concepts and Applications of Proteomics in Neuroscience
Hosp, F., & Mann, M. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.025 · Cited by 77 · see citing works
Vitamin C alleviates aging defects in a stem cell model for Werner syndrome
Li, Y., Zhang, W., Chang, L., Han, Y., Sun, L., Gong, X., Tang, H., Liu, Z., Deng, H., Ye, Y., et al. (2016) · Protein & Cell · doi:10.1007/s13238-016-0278-1 · Cited by 78 · see citing works
“On the other hand, elevated ROS levels have recently been known as a factor leading to heterochromatin disorganization (Frost et al., 2014).”
Backgroundp53 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 75 · see citing works
“Neuropathol Appl Neurobiol 30(1):19–29.”
Self-citationAlzheimer's disease: An acquired neurodegenerative laminopathy
Frost, B. (2016) · Nucleus · doi:10.1080/19491034.2016.1183859 · Cited by 74 · see citing works
“Identification of a neurodegenerative laminopathy Tauopathies are age-related progressive neurodegenerative disorders, including Alzheimer’s disease, which are pathologically characterized by aggregates of tau protein in the brain.36 Dominant mutations in the tau gene demonstrate that tau dysfunction is sufficient to…”
BackgroundInfluentialSelf-citationNitta, 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].”
BackgroundMethodInfluentialPathogenic 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
“We used flies at day 10 of adulthood, an age at which a moderate level of neurodegeneration can be detected in this model but before exponential decline in survivorship ( 22 , 24 ).”
Self-citationSahafnejad, Z., Ramazi, S., & Allahverdi, A. (2023) · Genes · doi:10.3390/genes14040873 · Cited by 71 · see citing works
“The most recent study shows a broad loss of heterochromatin in transgenic animal models and humans affected by AD have significantly increased gene expression [89].”
BackgroundAstrocyte senescence and SASP in neurodegeneration: tau joins the loop
Ungerleider, K., Beck, J. A., Lissa, D., Turnquist, C., Horikawa, I., Harris, B. T., & Harris, C. C. (2021) · Cell Cycle · doi:10.1080/15384101.2021.1909260 · Cited by 71 · see citing works
“Tau may directly cause DNA instability [78] or indirectly induce DNA damage through oxidative injury [79,80] (Figure 4).”
BackgroundLourenco, M. V., Ferreira, S. T., & Felice, F. G. D. (2015) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.03.003 · Cited by 71 · see citing works
Modeling the complex pathology of Alzheimer's disease in Drosophila
Fernandez-Funez, P., de Mena, L., & Rincon-Limas, D. E. (2015) · Experimental Neurology · doi:10.1016/j.expneurol.2015.05.013 · Cited by 69 · see citing works
“This heterochromatin loss occurred downstream of tau phosphorylation, was a consequence of oxidative stress and DNA damage, and induced aberrant gene expression (Frost et al., 2014).”
BackgroundRepetitive 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
“of TEs located in normally repressed genomic regions [70,90,133].”
BackgroundSinghal, N. K., Li, S., Arning, E., Alkhayer, K., Clements, R. J., Sarcyk, Z., Dassanayake, R. S., Brasch, N. E., Freeman, E. J., Bottiglieri, T., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4349-14.2015 · Cited by 70 · see citing works
“Decreased H3K9me2 has been shown to mediate chromatin relaxation, resulting in aberrant gene expression and neurodegeneration in Drosophila and mouse models of Alzheimer’s disease (AD) and in postmortem AD brain tissue (Frost et al., 2014).”
Background
- Authors
- Frost, B., Hemberg, M., Lewis, J., & Feany, M. B.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- University of Florida (US)
- Venue
- Nature Neuroscience
- Published
- 2014-01-26
- Volume
- 17
- Issue
- 3
- Pages
- 357-366
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4012297
- OpenAlex
- W2006588853
- Cited by
- 519
- References
- 61
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 43 · 2023: 50 · 2022: 51 · 2021: 47 · 2020: 41 · 2019: 28 · 2018: 40 · 2017: 36 · 2016: 28 · 2015: 31 · 2014: 17 · 2013: 1
- FWCI
- 22.29
- 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)
- PubMed Central (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, neurodegeneration, heterochromatin loss, chromatin relaxation, Alzheimer's disease, tauopathy, oxidative stress, DNA damage
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-20.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-20.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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