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Evolutionarily conserved regulators of tau identify targets for new therapies
Open accessAbstract
Tauopathies are neurodegenerative diseases that involve the pathological accumulation of tau proteins; in this family are Alzheimer disease, corticobasal degeneration, and chronic traumatic encephalopathy, among others. Hypothesizing that reducing this accumulation could mitigate pathogenesis, we performed a cross-species genetic screen targeting 6,600 potentially druggable genes in human cells and Drosophila. We found and validated 83 hits in cells and further validated 11 hits in the mouse brain. Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain. Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes. This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.
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TL;DR
A cross-species genetic screen in human cells and Drosophila identified conserved regulators of tau levels, three of which (USP7, RNF130, RNF149) converge on CHIP-mediated tau proteostasis. Adult knockdown of any of these three in a tauopathy mouse model lowered pathological tau and rescued memory deficits.
Key findings
- Parallel screens of 6,600 potentially druggable genes in human cells and Drosophila yielded 1,029 cell-screen gene hits and 613 Drosophila modifiers; 83 hits significantly altered tau levels in human 293T cells, and 11 of these significantly reduced endogenous tau by at least 15% in mouse brain after AAV8-shRNA delivery.
- USP7 is a deubiquitinase that stabilizes tau by counteracting CHIP-mediated polyubiquitination; its inhibitor P5091 increased tau polyubiquitination and lowered tau levels, and USP7 expression promoted tau aggregation in a seeding assay, while catalytically inactive USP7 (H456A) did not.
- RNF130 and RNF149 are E3 ligases that stabilize tau indirectly by promoting CHIP ubiquitination and degradation; depleting either extended CHIP's lifespan, and their effects on tau were abolished by CHIP depletion. IP/MS identified 288 RNF130 and 413 RNF149 putative interactors, with 185 overlapping.
- In adult PS19 tauopathy mice, doxycycline-inducible knockdown of USP7, RNF130, or RNF149 restored novel object discrimination and contextual fear-conditioning freezing, reduced Iba1 and GFAP staining, lowered proteopathic tau seeding activity, and reduced total tau, p-tau (pT205, pS396/S404), and oligomeric tau at 9 months; CHIP levels were significantly higher in aged RNF130 and RNF149 knockdown mice.
Methods
- Cell-based pooled shRNA screen (10 shRNAs/gene) in Daoy cells expressing EGFP-tau441/DsRed, with a secondary pooled gRNA/Cas9 screen of 858 ubiquitin-related genes; cells sorted for lowest and highest 5% EGFP/DsRed ratios and hits called by next-generation sequencing relative to bulk.
- Drosophila loss-of-function screen crossing a human WT tau441 ommatidial degeneration model with 3,898 inducible RNAi alleles targeting 2,645 Drosophila genes orthologous to 4,385 human genes; hits prioritized by cross-species overlap.
- Validation by tau ELISA and immunoblot in 293T cells, then AAV8-shRNA intracerebroventricular injection in neonatal mice; mechanistic work used co-immunoprecipitation, in vitro ubiquitination assays, cycloheximide chase, and IP/mass spectrometry; in vivo work used Dox-inducible shRNA in PS19 mice with behavioral testing (novel object recognition, contextual fear conditioning), FRET tau-biosensor seeding assays, and immunohistochemistry.
Limitations
- The authors note it would be worthwhile to test knockdown effects upon first appearance of behavioral abnormalities in PS19 mice (~6 months of age), since patients typically begin treatment after symptom onset; their knockdown began at 2 months.
- The authors state it would be important to better understand the molecular network and feedback mechanisms regulating CHIP, and to elucidate how USP7 switches target preference between tau and CHIP under healthy versus pathological conditions.
- Evident from the text: mechanistic dissection focused on only 3 of the 11 in vivo-validated hits, and the therapeutic rationale rests on mouse and cell models rather than human data.
Model-written summary. Check it against the paper before relying on it.
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- Findingown data§ Results
USP7 suppressed the CHIP-dependent lysine 27- and lysine 48-specific linkage polyubiquitination of tau in 293T cells.
“Likewise, USP7 suppressed the CHIP-dependent lysine 27- and lysine 48-specific linkage polyubiquitination of tau in 293T cells (Figure S3D).”
Quote in the paperSubstantial claim - Findingown data§ Results
From validation in human 293T cells, 83 hits showed significantly altered tau levels upon genetic knockdown.
“From this validation, 83 hits showed significantly altered tau levels upon genetic KD (Figures 1B, 1C, S1A, and S1B; Table S1 and S4B).”
Quote in the paperSubstantial claim - Findingown data§ Results
The degree of USP7-mediated deubiquitination was stronger for p-tau than for tau.
“However, the degree of USP7-mediated deubiquitination was stronger for p-tau, as reflected in the ratio of Ub-tau/total tau (Figure S4B).”
Quote in the paperNot a substantial claim - Findingown data§ Results
The effect of RNF130 or RNF149 shRNA on tau levels was abolished by depleting CHIP in mouse primary neurons.
“In addition, the effect of RNF130 or RNF149 shRNA on tau levels was also abolished by depleting CHIP in mouse primary neurons (Figures 4G and 4H).”
Quote in the paperSubstantial claim - Findingown data§ Results
At 5.5 months, CHIP levels were significantly greater in RNF130 KD mice.
“CHIP levels were significantly greater in RNF130 KD mice, but RNF149 KD had not affected CHIP levels yet at this age (Figures S7A–S7C).”
Quote in the paperNot a substantial claim
- Findingown data§ Results
At 5.5 months of age, knockdown of USP7, RNF130, or RNF149 reduced total and p-tau (pS396/S404) in PS19 mice.
“We found that the KD of USP7, RNF130, or RNF149 reduced total and p-tau (pS396/S404).”
Quote in the paperSubstantial claim - Findingown data§ Results
CHIP and USP7 interact with each other independently of tau.
“Interestingly, we found that CHIP-IP or USP7-IP could pull down USP7 or CHIP, respectively, as well as tau (Figures 3A and 3B), and the USP7 inhibitor (P5091) did not interfere with CHIP-tau interaction (data not shown), showing that CHIP and USP7 interact with each other independently of tau (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data§ Results
Brain homogenates from PS19 mice with target gene knockdown (USP7, RNF130, RNF149) showed markedly reduced proteopathic tau seeding activities compared with PS19 control mice.
“Brain homogenates from PS19 mice with target gene KD (PS19/USP7 KD, PS19/RNF130 KD, and PS19/RNF149 KD mice) showed markedly reduced proteopathic tau seeding activities as compared with those from PS19 control mice (PS19/Ctrl) (Figure 6H, top right and lower panel).”
Quote in the paperSubstantial claim - Findingown data§ Results
CHIP levels were significantly higher in aged RNF130 KD and RNF149 KD mice than in control PS19 mice.
“Notably, CHIP levels were significantly higher in the aged RNF130 KD and RNF149 KD mice than those in control PS19 mice (Figure 7C).”
Quote in the paperSubstantial claim - Findingown data§ Results
The selective USP7 inhibitor P5091 significantly increased tau polyubiquitination in a time- and dose-dependent manner in both 293T cells and hESC-derived neurons.
“IB analysis of tau IP samples revealed that the selective USP7 inhibitor (P5091) significantly increased tau polyubiquitination in a time- and dose-dependent manner in both 293T cells (Figure 2A) and human embryonic stem cell (hESC)-derived neurons (Figure 2B).”
Quote in the paperSubstantial claim - Findingown data§ Results
PS19 mice with target gene knockdown had less microgliosis (reduced Iba1 staining) in the cortex, hippocampus CA1, and dentate gyrus compared with PS19 control mice.
“All PS19 mice with target gene KD had less microgliosis illustrated by the reduced Iba1 staining (Figures 6F and S6A) in the cortex, hippocampus CA1, and dentate gyrus (DG) compared with PS19 control mice.”
Quote in the paperSubstantial claim - Findingown data§ Results
p-tau and oligomeric tau were reduced to a greater extent than total tau in PS19/KD mice.
“Interestingly, p-tau and oligomeric tau were reduced to a greater extent than total tau.”
Quote in the paperNot a substantial claim - Findingown data§ Results
At 9 months of age, PS19/KD mice had markedly lower levels of total tau and pathological forms of tau (p T205, p S396/S404 residues, and oligomeric tau) than controls.
“At 9 months of age, PS19/KD mice had markedly lower levels of total tau and pathological forms of tau (p T205, p S396/S404 residues, and oligomeric tau) (Figures 7A and 7B).”
Quote in the paperSubstantial claim - Findingown data§ Results
A number of hits converge on functional pathways, as illustrated for proteins in the Sumo conjugation pathway.
“Notably, the data revealed that a number of hits converge on functional pathways, as illustrated for proteins in the Sumo conjugation pathway (Tables S1A and S4B).”
Quote in the paperNot a substantial claim - Findingown data§ Results
USP7 and tau interact in the mouse brain.
“Our reciprocal co-immunoprecipitation (coIP) results indicate the interaction between USP7 and tau in the mouse brain (Figure 2G).”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Genetic knockdown of USP7, RNF130, or RNF149 in the brain mitigated memory and learning deficits in PS19 mice.
“Here, we found that the genetic KD of USP7, RNF130, or RNF149 in the brain reduced pathological tau species (p-tau and tau oligomers) and mitigated memory and learning deficits and other pathological features in a tauopathy mouse model (PS19 mice).”
Quote in the paperSubstantial claim - Findingown data§ Results
FYN limits the degradation of both RNF130 and RNF149, extending their respective half-lives.
“Instead, CHX chase analysis of 293T cells co-expressing RNF130 or RNF149 with FYN revealed that FYN limits the degradation of both RNF130 and RNF149, extending their respective half-lives (Figure 5D).”
Quote in the paperSubstantial claim - Findingown data§ Results
Knockdown of the 11 candidate tau regulators significantly reduced endogenous tau levels by at least 15% in the mouse brain.
“The IB analysis of brain homogenates from the injected mice revealed that KD of the 11 candidate tau regulators significantly reduced endogenous tau levels by at least 15% (Figures 1E and 1F; Table S5).”
Quote in the paperSubstantial claim - Findingown data§ Results
Depletion of CHIP completely abolished the accumulation of polyubiquitinated tau and the reduction of tau levels in 293T cells and mouse primary cortical neurons typically seen after USP7 inhibition.
“We found that depletion of CHIP completely abolished the accumulation of polyubiquitinated tau (Figures 3D and 3E) and reduction of tau levels in 293T cells (Figure 3F) and in mouse primary cortical neurons (Figures 3G and S3C) typically seen after USP7 inhibition.”
Quote in the paperSubstantial claim - Findingown data§ Results
CHIP had no effect on the ubiquitination of either RNF130 or RNF149.
“CHIP had no effect on the ubiquitination of either protein (Figures 5A and 5B).”
Quote in the paperNot a substantial claim - Findingown data§ Results
RNF130 and RNF149 are heavily poly-ubiquitinated.
“A cellular ubiquitination assay revealed that RNF130 and RNF149 are heavily poly-ubiquitinated and that RNF130 ubiquitination was decreased by RNF149 expression, whereas RNF149 ubiquitination was unaffected by RNF130.”
Quote in the paperSubstantial claim - Findingcitation§ Results
Heavy phosphorylation of tau by GSK3β significantly increased CHIP-mediated ubiquitination of tau.
“Consistent with previous studies, heavy phosphorylation of tau by the GSK3β kinase significantly increased CHIP-mediated ubiquitination of tau.”
Quote in the paperNot a substantial claim - Findingown data§ Results
USP7 deubiquitinated both tau and p-tau.
“We found that USP7 deubiquitinated both tau and p-tau (Figure S4A).”
Quote in the paperSubstantial claim - Findingown data§ 3 Biotech. 2020; 10:193
The study identified and validated 82 regulators of tau protein levels.
“We identified and validated 82 regulators of tau protein levels and pursued mechanistic studies of three of them.”
Quote in the paperSubstantial claim - Findingown data§ Results
At 5.5 months, RNF149 KD had not affected CHIP levels yet.
“CHIP levels were significantly greater in RNF130 KD mice, but RNF149 KD had not affected CHIP levels yet at this age (Figures S7A–S7C).”
Quote in the paperNot a substantial claim - Findingown data§ Results
P5091 negatively correlated with tau levels in human neuroblastoma cells and hESC-derived neurons in a dose-dependent manner.
“In addition, P5091 negatively correlated with tau levels in human neuroblastoma cells and hESC-derived neurons in a dose-dependent manner (Figure 2C).”
Quote in the paperSubstantial claim - Findingown data§ Results
The Drosophila screen identified 613 genes that modulated tau-induced degeneration, orthologous to 1,674 human genes.
“This Drosophila screen identified 613 genes that modulated tau-induced degeneration, which are orthologous to 1,674 human genes (Figure 1A-panel 2; Tables S3B and 3C).”
Quote in the paperSubstantial claim - Findingown data§ Results
Depleting either RNF130 or RNF149 extended CHIP's lifespan.
“We found that depleting either RNF130 or RNF149 extended CHIP’s lifespan, suggesting that both act to destabilize CHIP (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data§ Results
RNF130 and RNF149 are phosphorylated on their tyrosine residues in the presence of FYN.
“Next, we performed IB analysis using phosphor-tyrosine antibodies, and we found that RNF130 and RNF149 are phosphorylated on their tyrosine residues in the presence of FYN (Figure 5E).”
Quote in the paperSubstantial claim - Findingown data§ Results
Next-generation sequencing identified enriched/depleted shRNAs and gRNAs that target 1,029 genes.
“Next-generation sequencing of these subpopulations as well as the bulk unsorted cell population identified enriched/depleted shRNAs and gRNAs that target 1,029 genes (Figure 1A; Table S2).”
Quote in the paperSubstantial claim - Findingown data§ Results
Depletion of CHIP nullified the effect of USP7 expression on tau levels in 293T cells.
“Notably, the depletion of CHIP nullified the effect of USP7 expression on tau levels in 293T cells (Figure 3I).”
Quote in the paperSubstantial claim - Findingown data§ Results
Knockdown of target genes mitigated abnormal astrocytic activation, shown by reduced GFAP signal in the cortex and hippocampus compared with controls.
“KD of target genes also mitigated abnormal astrocytic activation, as demonstrated by the reduced Glial Fibrillary acidic protein (GFAP) signal in the cortex and hippocampus compared with controls (Figures 6G and S6B).”
Quote in the paperSubstantial claim - Findingown data§ Results
Expression of either RNF130 or RNF149 in 293T cells markedly increased CHIP ubiquitination.
“Conversely, expression of either RNF130 or RNF149 in 293T cells markedly increased CHIP ubiquitination (Figure 4D).”
Quote in the paperSubstantial claim - Findingnone given§ Discussion
Adult knockdown of either RNF130 or RNF149 in the brain was well tolerated.
“That adult KD of either of these genes in the brain was well tolerated, coupled with the fact that haploinsufficiency for either protein is tolerated in humans (https://gnomad.broadinstitute.org/) bodes well for their potential druggability.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
In our cellular tau aggregation model, USP7 promoted tau aggregation upon proteopathic tau seeding.
“In our cellular tau aggregation model, USP7 promoted tau aggregation upon proteopathic tau seeding.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Molecular signatures of tau pathology (p-tau) have already appeared in PS19 mice by 2 months after birth.
“Initiation of the KD of USP7, RNF130, or RNF149 in PS19 mice at 2 months after birth, by which time molecular signatures of tau pathology (p-tau) have already appeared (Figure 6C),”
Quote in the paperSubstantial claim - Interpretationreasoning§ Results
RNF130 and RNF149 modulate tau levels via other mediators.
“We reasoned, therefore, that RNF130 and RNF149 modulate tau levels via other mediators.”
Quote in the paperSubstantial claim - Study design and conductown data§ Results
By bilateral injection of AAV8-shRNA at 6-10 × 10^10 particles per hemisphere, suppression of the target gene by ≤50% was achieved in the mouse brain without toxicity.
“By bilateral injection of AAV8-shRNA at 6–10 × 1010 particles per hemisphere, we achieved suppression of the target gene by ≤50% in the mouse brain without toxicity, showing no notable abnormality until 3 weeks before harvest (Figure S2B).”
Quote in the paperSubstantial claim - Study design and conductown data§ Results
shRNA expression was efficiently switched on upon the change in diet.
“To test the gene KD efficiency, we co-injected P0 mice with AAV containing inducible shRNA and AAV containing tetracycline-transactivator (TTA) and then fed them the Dox diet until 3 weeks of age; shRNA expression was efficiently switched on upon the change in diet (Figure 6B).”
Quote in the paperSubstantial claim - Interpretationcitation§ 3 Biotech. 2020; 10:193
Elevated tau protein levels are causally linked to disease pathogenesis.
“Such findings strongly suggest that elevated tau protein levels are causally linked to disease pathogenesis—and led us to hypothesize that there must be genes and molecular pathways that regulate tau levels—and manipulation of these genes can lower tau levels, providing a therapeutic strategy for a whole family of currently untreatable diseases.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
RNF130 and RNF149 regulate tau in a CHIP-dependent manner.
“We therefore propose that RNF130 and RNF149 also regulate tau in a CHIP-dependent manner (Figure 4I).”
Quote in the paperSubstantial claim - Interpretationown data§ Results
Downregulation of the target genes during adulthood can successfully ameliorate memory deficits in PS19 mice.
“Our data show that downregulation of our target genes during adulthood can successfully ameliorate memory deficits in PS19 mice.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
USP7 stabilizes tau by deubiquitinating it.
“These data demonstrate that USP7 stabilizes tau by deubiquitinating it (Figure 2F).”
Quote in the paperSubstantial claim- Rests on an assumption: USP7 is a deubiquitinase that cleaves ubiquitin, thereby protecting its substrates from proteasomal or autophagic degradation.
- Premisecitation§ Results
CHIP plays a critical role in the degradation of hyperphosphorylated tau (p-tau).
“Knowing that CHIP plays a critical role in the degradation of hyperphosphorylated tau (p-tau),16”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ Results
USP7, RNF130, and RNF149 are in vivo regulators of tau levels.
“Collectively, our data demonstrate that USP7, RNF130, and RNF149 are in vivo regulators of tau levels, play an important role in tauopathy pathogenesis, and represent potential therapeutic targets for decreasing tau levels and mitigating tau pathology (Figure 7D).”
Quote in the paperSubstantial claim - Interpretationown data§ Results
RNF149 stabilizes RNF130 by suppressing RNF130 ubiquitination.
“These data suggest that RNF149 stabilizes RNF130 by suppressing RNF130 ubiquitination.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
USP7 stabilizes tau by protecting it from CHIP-mediated ubiquitination.
“These data demonstrate that USP7 stabilizes tau by protecting it from CHIP-mediated ubiquitination (Figure 3J).”
Quote in the paperSubstantial claim - Interpretationown data§ Results
USP7, RNF130, and RNF149 play an important role in tauopathy pathogenesis.
“Collectively, our data demonstrate that USP7, RNF130, and RNF149 are in vivo regulators of tau levels, play an important role in tauopathy pathogenesis, and represent potential therapeutic targets for decreasing tau levels and mitigating tau pathology (Figure 7D).”
Quote in the paperSubstantial claim - Premisecitation§ 3 Biotech. 2020; 10:193
The notion that protein levels can be pathogenic is supported by rare genetic forms of these diseases, such as frontotemporal dementia caused by an extra copy of the MAPT gene.
“The notion that protein levels can be pathogenic is supported by rare genetic forms of these diseases, such as frontotemporal dementia caused by an extra copy of the MAPT gene.11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ Discussion
Knockdown of RNF130 and RNF149 reduces tau levels through stabilizing CHIP.
“The discovery that KD of RNF130 and RNF149 reduces tau levels through stabilizing CHIP is quite exciting and opens up the possibility of identifying small molecules that could inhibit their activity and, if safe, be used to lower tau levels.”
Quote in the paperSubstantial claim - Study design and conductnone given§ Discussion
Using a Dox-inducible system to knock down candidate genes in adult PS19 mice eliminates the chance for secondary non-specific effects and potential compensatory mechanisms that might arise from loss of gene function during development.
“First, using a Dox-inducible system to knock down our candidate genes in adult PS19 mice eliminates the chance for secondary non-specific effects and potential compensatory (or pathogenic) mechanisms that might arise due to the loss of the gene’s function during development.”
Quote in the paperSubstantial claim- Rests on an assumption: ASO therapies are invasive.
- Rests on an assumption: Individuals at risk for AD need to be treated for decades.
- Interpretationown data§ Discussion
Two independent screens uncovered genes whose molecular functions converge on CHIP.
“The fact that two independent screens uncovered genes whose molecular functions converge on CHIP highlights a central role of CHIP in maintaining tau proteostasis in the brain.”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
Haploinsufficiency for either RNF130 or RNF149 protein is tolerated in humans.
“That adult KD of either of these genes in the brain was well tolerated, coupled with the fact that haploinsufficiency for either protein is tolerated in humans (https://gnomad.broadinstitute.org/) bodes well for their potential druggability.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites https://gnomad.broadinstitute.org/
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data§ Discussion
Our results suggest that USP7 can indirectly destabilize tau by enhancing CHIP activity.
“For example, our results suggest that USP7 can stabilize tau directly while also indirectly destabilizing it by enhancing CHIP activity.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Discussion
CHIP has a central role in maintaining tau proteostasis in the brain.
“The fact that two independent screens uncovered genes whose molecular functions converge on CHIP highlights a central role of CHIP in maintaining tau proteostasis in the brain.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Tau may be a more favorable substrate for USP7 activity, especially under pathological conditions.
“Moreover, suppressing USP7 exerted beneficial effects in the tauopathy mice, suggesting tau may be a more favorable substrate for USP7 activity, especially under pathological conditions.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Suppressing USP7 exerted beneficial effects in tauopathy mice.
“Moreover, suppressing USP7 exerted beneficial effects in the tauopathy mice, suggesting tau may be a more favorable substrate for USP7 activity, especially under pathological conditions.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Our results suggest that USP7 can stabilize tau directly.
“For example, our results suggest that USP7 can stabilize tau directly while also indirectly destabilizing it by enhancing CHIP activity.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Our data suggest that USP7 has a stronger preference for deubiquitinating tau than CHIP.
“Our data suggest that USP7 has a stronger preference for deubiquitinating tau than CHIP.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
USP7 could be a key factor in propagating tau pathology.
“USP7 could be a key factor in propagating tau pathology.”
Quote in the paperSubstantial claim- Rests on an assumption: Transcellular propagation of tau aggregation underlies disease progression.
- Interpretationown data§ Discussion
Even modest suppression of these genes in adult tauopathy mice benefited learning and memory deficits.
“Even the modest suppression of these genes in adult tauopathy mice benefited the learning and memory deficits, proving that reducing tau levels could be an attractive therapeutic strategy for tauopathies to delay or prevent disease progression.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Starting from an unbiased pooled genetic screen, we identified several genes that converge onto CHIP-mediated control of tau proteostasis.
“In summary, starting from an unbiased pooled genetic screen, we identified several genes that converge onto CHIP-mediated control of tau proteostasis.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
All three (USP7, RNF130, RNF149) converge on CHIP to influence tau proteostasis.
“Although USP7, RNF130, and RNF149 have never been associated with each other before, all three converge on CHIP to influence tau proteostasis.”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
Reducing tau levels could be an attractive therapeutic strategy for tauopathies to delay or prevent disease progression.
“Even the modest suppression of these genes in adult tauopathy mice benefited the learning and memory deficits, proving that reducing tau levels could be an attractive therapeutic strategy for tauopathies to delay or prevent disease progression.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 44
- Probably not a substantial claim. 20
It may state two separate claims as one.
Findingown data§ ResultsUSP7 expression abrogated tau ubiquitination, whereas a catalytically inactive USP7 mutant (H456A; mtUSP7) had no such effect.
“Conversely, USP7 expression abrogated tau ubiquitination; a catalytically inactive USP7 mutant (H456A; mtUSP7) had no such effect (Figure 2D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsshRNA-mediated lowering of either RNF130 or RNF149 reduced tau levels in cells and mouse brains.
“The fact that shRNA-mediated lowering of either protein reduced tau levels in cells (Figure 1B) and mouse brains (Figures 1E and 1F) argued against them being ubiquitin ligases for tau.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ 1 ∙ Hyun-Hwan JeongKnockdown of each of USP7, RNF130, or RNF149 in adult tauopathy mice reduced tau levels and rescued the disease phenotypes.
“Knockdown of each of these three genes in adult tauopathy mice reduced tau levels and rescued the disease phenotypes.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsPS19 mice displayed typical tau phosphorylation (pSer202/pThr205) in the brain at 2 months of age, but USP7 and RNF130 suppression reduced the levels of human tau and p-tau, respectively.
“PS19 mice displayed the typical tau phosphorylation (pSer202/pThr205) in the brain at 2 months of age, but USP7 and RNF130 suppression reduced the levels of human tau and p-tau, respectively (Figure 6C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsUSP7 deubiquitinated CHIP in human cells, but the polyubiquitination of USP7 was not altered by CHIP.
“Furthermore, USP7 deubiquitinated CHIP in human cells (Figure S3A), but the polyubiquitination of USP7 was not altered by CHIP (Figure S3B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsThe RNF130-RNF149 interaction, along with the RNF149-FYN, RNF130-CHIP, and RNF149-CHIP interactions, was confirmed.
“Using the coIP assay in 293T cells, we confirmed the RNF130-RNF149 interaction, along with the RNF149-FYN, RNF130-CHIP, and RNF149-CHIP interactions (Figure 4B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsThe tau-biosensor cell line formed numerous aggregates after 24 h transduction with aged PS19 brain lysates, but no aggregates were detected after transduction with age-matched WT brain lysates.
“The tau-biosensor cell line formed numerous aggregates after 24 h of transduction with aged PS19 brain lysates, but no aggregates were detected after transduction with age-matched WT brain lysates (Figure 6H, top left panels).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsNeither direct binding nor significant ubiquitination of tau by either RNF130 or RNF149 was detected.
“In fact, we detected neither direct binding nor significant ubiquitination of tau by either RNF130 or RNF149 (data not shown).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsUSP7 overexpression significantly increased tau levels, whereas mtUSP7 overexpression had a minimal effect on the tau level.
“USP7 overexpression significantly increased tau levels, whereas mtUSP7 overexpression had a minimal effect on the tau level (Figure 2E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsThe CHIP-tau interaction was reduced by the presence of USP7, while the USP7-tau interaction was less affected by CHIP.
“In coIP experiments, the CHIP-tau interaction was reduced by the presence of USP7 protein, while the USP7-tau interaction was less affected by CHIP.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsUSP7 expression completely abolished CHIP-mediated tau ubiquitination but not tau ubiquitination by CUL4A.
“Supporting this result, expression of USP7 completely abolished the CHIP-mediated tau ubiquitination but not tau ubiquitination by CUL4A (also identified in our screen); de-ubiquitination of tau occurred only after CHIP polyubiquitinated tau (Figure 3H).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsRNF130 ubiquitination was decreased by RNF149 expression, whereas RNF149 ubiquitination was unaffected by RNF130.
“A cellular ubiquitination assay revealed that RNF130 and RNF149 are heavily poly-ubiquitinated and that RNF130 ubiquitination was decreased by RNF149 expression, whereas RNF149 ubiquitination was unaffected by RNF130.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsNeither RNF130 nor RNF149 affected FYN ubiquitination or stability in human cells.
“We explored whether RNF130 and RNF149 regulate tau levels through FYN but found that neither affected FYN ubiquitination or stability in human cells.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsIP/MS identified 288 putative interactors for RNF130 and 413 for RNF149, with 185 of the interactors overlapping.
“This effort identified 288 putative interactors for RNF130 and 413 for RNF149, with 185 of the interactors overlapping (Figure 4A; Table S6).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsAt 8 months of age, PS19 mice exhibited less freezing than age-matched WT mice in the contextual fear-conditioning task, but knockdown of USP7, RNF130, and RNF149 rescued this behavior.
“At 8 months of age, PS19 mice exhibited less freezing than the age-matched WT mice in the contextual fear-conditioning task, a test of hippocampus-dependent memory, but again, KD of USP7, RNF130, and RNF149 rescued this behavior (Figure 6E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsTau aggregation was increased upon expression of USP7 but not catalytically inactive USP7 (mtUSP7), and this increase was reversed by the USP7 inhibitor.
“Tau aggregation was increased upon the expression of USP7 but not a catalytically inactive USP7 (mtUSP7), which was reversed by the USP7 inhibitor (Figures S4D and S5).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsRNF130 and RNF149 overexpression increased endogenous tau levels, but this increase was abolished by depleting CHIP.
“RNF130 and RNF149 overexpression increased endogenous tau levels, but this increase was abolished by depleting CHIP (Figures 4E and 4F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsTau's microtubule-binding repeat region (MTBR) is necessary and sufficient to bind USP7.
“IB analysis of tau IP samples showed that tau’s microtubule-binding repeat region (MTBR) is necessary (Figure 2I) and sufficient (Figure 2J) to bind USP7.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ 3 Biotech. 2020; 10:193Genetic knockdown of USP7, RNF130, or RNF149 in the brain reduced pathological tau species (p-tau and tau oligomers) and mitigated memory and learning deficits and other pathological features in a tauopathy mouse model.
“Specifically, we found that genetic knockdown (KD) of USP7, RNF130, or RNF149 in the brain reduced pathological tau species (p-tau and tau oligomers) and mitigated memory and learning deficits and other pathological features in a tauopathy mouse model.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsRNF149 delayed RNF130 degradation but not vice versa.
“Notably, we observed that RNF149 delayed RNF130 degradation but not vice versa (Figure 5C).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown data§ ResultsIn the novel object task, PS19 mice were unable to discriminate between novel and familiar objects; knockdown of USP7, RNF130, or RNF149 restored object discrimination.
“In the novel object task, PS19 mice were unable to discriminate between novel and familiar objects; KD of USP7, RNF130, or RNF149 restored object discrimination (Figure 6D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown data§ ResultsAdult knockdown of USP7, RNF130, or RNF149 mitigates tau pathologies in PS19 mice.
“Adult knockdown of USP7, RNF130, or RNF149 mitigates tau pathologies”
Quote in the paperSubstantial claim- Rests on an assumption: Dysregulation of tau proteostasis is involved in tau-related pathology.
It may state two separate claims as one.
Interpretationown data§ 1 ∙ Hyun-Hwan JeongThis study identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.
“This study thus identifies several points of intervention to reduce tau levels and demonstrates that reduction of tau levels via regulation of this pathway is a viable therapeutic strategy for Alzheimer disease and other tauopathies.”
Quote in the paperSubstantial claim- Rests on an assumption: There is currently no treatment for any of the tauopathies.
It may state two separate claims as one.
Premisecitation§ 3 Biotech. 2020; 10:193Reducing endogenous tau levels prevents amyloid-β-induced deficits in an Alzheimer disease mouse model and protects mice against excitotoxicity.
“Conversely, reducing endogenous tau levels prevents amyloid-β-induced deficits in an AD mouse model and protects mice against excitotoxicity.13”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ 1 ∙ Hyun-Hwan JeongThree hits (USP7, RNF130, and RNF149) converge on CHIP to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain.
“Three of these hits (USP7, RNF130, and RNF149) converge on the C terminus of Hsc70-interacting protein (CHIP) to regulate tau levels, highlighting the role of CHIP in maintaining tau proteostasis in the brain.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
Premisecitation§ ResultsRNF130 and RNF149 are E3 ubiquitin ligases that promote the degradation of substrate proteins.
“RNF130 and RNF149 are E3 ubiquitin ligases that promote the degradation of substrate proteins.22”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
Premisecitation§ ResultsIn tau-biosensor cells (Tau RD P301S FRET Biosensor), YFP and CFP form a FRET pair upon induction of tau aggregation.
“To measure tau seeding activity, we utilized the tau-biosensor cells (Tau RD P301S FRET Biosensor cell), in which YFP and CFP form a FRET pair upon the induction of tau aggregation.27”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ ResultsCHIP interacts with tau's MTBR and ubiquitinates tau for proteasomal degradation.
“A previous study reported that the CHIP interacts with tau’s MTBR and ubiquitinates tau for proteasomal degradation.17”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation§ 3 Biotech. 2020; 10:193CHIP polyubiquitinates and degrades tau.
“CHIP polyubiquitinates and degrades tau.16”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ ResultsFYN can phosphorylate and stabilize both RNF130 and RNF149, thereby indirectly stabilizing tau.
“These findings demonstrate that FYN can phosphorylate and stabilize both RNF130 and RNF149, thereby indirectly stabilizing tau.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ 3 Biotech. 2020; 10:193p300/CBP acetylates and stabilizes tau, leading to its accumulation and toxicity.
“p300/CBP acetylates and stabilizes tau, leading to its accumulation and toxicity.18”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [20]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation§ 3 Biotech. 2020; 10:193Reduction of tau acetylation decreases total tau and acetylated tau, tau-related pathology, and memory deficits in a tauopathy mouse model.
“However, reduction of tau acetylation has been shown to decrease total tau and acetylated tau, tau-related pathology, and memory deficits in a tauopathy mouse model.19”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation§ ResultsPS19 mice express human mutant tau (1N4R P301S) at five times the level of the endogenous mouse protein and recapitulate many features of human tauopathies.
“We knocked down USP7, RNF130, or RNF149 in adult PS19 mice, which express human mutant tau (1N4R P301S) at five times the level of the endogenous mouse protein and recapitulate many features of human tauopathies.26”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation§ ResultsFYN tyrosine kinases phosphorylate tau at tyrosine 18 (Y18) and enhance tau pathology in cell and mouse models.
“FYN tyrosine kinases phosphorylate tau at tyrosine 18 (Y18) and enhance tau pathology in cell and mouse models.24”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ ResultsUSP7 stabilizes tau, including phosphorylated tau species, thereby promoting tau aggregation in cells.
“These data demonstrate that USP7 stabilizes tau, including phosphorylated tau species, thereby promoting tau aggregation in cells.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ ResultsCHIP ubiquitinates tau (especially p-tau) and thereby regulates its degradation and aggregation.
“CHIP ubiquitinates tau (especially p-tau) and thereby regulates its degradation and aggregation.16”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Premisecitation§ 3 Biotech. 2020; 10:193NUAK1 haploinsufficiency reduced tau levels by 15%-20% in P301S tau transgenic (PS19) mice, and this modest reduction was sufficient to reverse multiple disease features.
“Notably, NUAK1 haploinsufficiency reduced tau levels by 15%–20% in P301S tau transgenic (PS19) mice, a model of neurodegenerative tauopathy and AD, and even this modest reduction in tau protein was sufficient to reverse multiple disease features.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown data§ ResultsUSP7, RNF130, and RNF149 represent potential therapeutic targets for decreasing tau levels and mitigating tau pathology.
“Collectively, our data demonstrate that USP7, RNF130, and RNF149 are in vivo regulators of tau levels, play an important role in tauopathy pathogenesis, and represent potential therapeutic targets for decreasing tau levels and mitigating tau pathology (Figure 7D).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Premisecitation§ 3 Biotech. 2020; 10:193In mice, overexpression of wild-type tau leads to age-dependent cognitive impairment and synaptic dysfunction.
“Similarly, in mice, overexpression of wild-type (WT) tau leads to age-dependent cognitive impairment and synaptic dysfunction.12”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ ResultsPS19 mouse brains display tau seeding activity, suggesting misfolded tau present in brain homogenate can enhance tau aggregation via a prion-like mechanism.
“Previous reports found that PS19 mouse brains display tau seeding activity, suggesting that misfolded tau present in the brain homogenate can enhance tau aggregation via a prion-like mechanism.27”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
Study design and conductown data§ DiscussionGenes whose knockdown significantly decreased or increased tau protein levels by >15% in ≥2/3 shRNAs from biological quadruplicates in comparison to nontargeting shRNA were subjected to additional immunoblotting assay (p<0.1).
“Genes whose knockdown significantly decreased or increased tau protein levels by >15% in ≥2/3 shRNAs from biological quadruplicates in a comparison to nontargeting shRNA were subjected to the additional immunoblotting assay (p<0.1) in which tau level was compared to nontargeting (NT)shRNA and selected as hits based on same criteria as ELISA assay.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
Study design and conductnone given§ DiscussionAll procedures were reviewed and approved by the Baylor College of Medicine Institutional Animal Care and Use Committee in accordance with the guidelines of the US National Institutes of Health.
“All procedures were reviewed and approved by the Baylor College of Medicine Institutional Animal Care and Use Committee in accordance with the guidelines of the US National Institutes of Health.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductcitation§ DiscussionThe knockdown efficiency of each shRNA in pAAV was tested in Neuro2A cells.
“The knockdown efficiency of each shRNA in pAAV was tested in Neuro2A cell as previously described.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone given§ DiscussionSamples with <50% of average protein concentration were excluded.
“samples with <50% of average protein concentration were excluded.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DiscussionSeveral studies have demonstrated a protective function for CHIP in other neurological diseases such as stroke, intracerebral hemorrhage, PD, and polyglutamine diseases.
“In fact, several studies have demonstrated a protective function for CHIP in the context of other neurological diseases such as stroke, intracerebral hemorrhage, PD, and polyglutamine diseases29”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. It may state two separate claims as one.
Interpretationreasoning§ DiscussionCHIP upregulation could possibly be neuroprotective in multiple neurological diseases, serving as a promising therapeutic strategy.
“CHIP upregulation could possibly be neuroprotective in multiple neurological diseases, serving as a promising therapeutic strategy.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductown data§ DiscussionFor statistical reliability, three replicates were studied for each group (RFP/GFP, RNF130-3Xflag, RNF149-3Xflag) by independent immunoprecipitation/mass-spectrometry experiments.
“For statistical reliability, we studied three replicates for each group (RFP/GFP, RNF130-3Xflag, RNF149-3Xflag) by independent IP/MS experiments.”
Quote in the paperSubstantial claimProbably not a substantial claim.
Study design and conductnone given§ DiscussionPreference index during the training phase, which should be 50%:50%, was used as an environmental control to rule out the location effect of the objects.
“Preference index during the training phase, which should be 50%:50%, was used as an environmental control to rule out the location effect of the objects.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DiscussionPrevious studies have tested the therapeutic efficacy of decreasing tau levels in a mouse model of tauopathy and non-human primates via ICV infusion of antisense oligonucleotides (ASOs) targeting human tau mRNA.
“Previous studies have tested the therapeutic efficacy of decreasing tau levels in a mouse model of tauopathy and non-human primates via the ICV infusion of antisense oligonucleotides (ASOs) targeting human tau mRNA.28”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: ASO therapies are invasive.
- Rests on an assumption: Individuals at risk for AD need to be treated for decades.
Probably not a substantial claim.
Study design and conductown data§ DiscussionIn the bivariate plot, to assess the number of FRET-positive cells we created a gate by using the FRET-negative signal exhibited by biosensor cell treated with lipofectamine alone and the FRET-positive signal exhibited by 293T cells expressing CFP fused with YFP.
“In this bivariate plot, to assess the number of FRET-positive cells we created a gate by using the FRET-negative signal exhibited by biosensor cell treated with lipofectamine alone and the FRET-positive signal exhibited by 293T cells expressing CFP fused with YFP.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DiscussionNUAK1 phosphorylates tau at Ser356 to reduce its ubiquitination by CHIP.
“This is particularly striking in light of our previous finding that NUAK1 phosphorylates tau at Ser356 to reduce its ubiquitination by CHIP.15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DiscussionUSP7 has a greater affinity for the p53 E3 ligase MDM2 than it does for p53, and so it protects MDM2 from auto-ubiquitination, ultimately leading to proteasomal degradation of p53.
“In that scenario, USP7 has a greater affinity for the p53 E3 ligase MDM2 than it does for p53, and so it protects MDM2 from auto-ubiquitination, ultimately leading to the proteasomal degradation of p53.35”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DiscussionUpon external stimulation, USP7 shifts from MDM2 to p53, causing MDM2 to be degraded and instead stabilizing p53.
“Upon external stimulation, however, USP7 shifts from MDM2 to p53, causing MDM2 to be degraded and instead stabilizing p53.36”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [36]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [37]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Premisecitation§ DiscussionMutations in the CHIP gene have been found in several human patients with various forms of spinocerebellar ataxia (SCA; SCA16 and SCA48).
“In addition, mutations in the CHIP gene have been found in several human patients with various forms of spinocerebellar ataxia (SCA; SCA16 and SCA48).34”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. It may state two separate claims as one.
Study design and conductown data§ DiscussionFor the screen, three independent experimental sets were performed, and the effect of siRNAs within each set was compared to the non-target siRNA controls by analysis of variance followed by Dunnet's and Tukey's post hoc tests to select for siRNAs that were significantly decreased or increased.
“For the screen, we performed three independent experimental sets and compared the effect of siRNAs within each set to the non-target siRNA controls by analysis of variance followed by Dunnet’s and Tukey’s post hoc tests to select for the siRNAs that were significantly decreased or increased.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisecitation§ DiscussionIn AD, tau pathology follows a predictable progression, which is classified by Braak stages and correlates with disease symptomatology.
“In AD, tau pathology follows a predictable progression, which is classified by Braak stages and correlates with the disease symptomatology.38”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
There is currently no treatment for any of the tauopathies.
“There is currently no treatment for any of these disorders.”
The paper relies on this without support.
Cross-species conservation would likely point to biologically conserved pathways.
“We prioritized targets based on the overlap between these two screening strategies (Figure 1A-panel 3), reasoning that cross-species conservation would likely point to biologically conserved pathways.”
The paper relies on this without support.
Reducing tau levels would result in reduction of acetylated tau as well as all other modified tau species.
“Thus, we rationalized that reducing tau levels would result in reduction of acetylated tau as well as all other modified tau species.”
The paper relies on this without support.
USP7 is a deubiquitinase that cleaves ubiquitin, thereby protecting its substrates from proteasomal or autophagic degradation.
“USP7 is a deubiquitinase that cleaves ubiquitin, thereby protecting its substrates from proteasomal or autophagic degradation.”
The paper relies on this without support.
ASO therapies are invasive.
“given the invasive nature of ASO therapies”
The paper relies on this without support.
Individuals at risk for AD need to be treated for decades.
“the need to treat individuals at risk for decades”
The paper relies on this without support.
Dysregulation of tau proteostasis is involved in tau-related pathology.
“The dysregulation of tau proteostasis is clearly involved in tau-related pathology”
The paper relies on this without support.
Transcellular propagation of tau aggregation underlies disease progression.
“Transcellular propagation of tau aggregation, in which tau pathology moves from one neuron to the next, underlies disease progression.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
USP7 inhibitor identifier differs in the methods
MinorThe results identify the USP7 inhibitor as P5091, while the tau aggregation assay methods call it P5019.
“the selective USP7 inhibitor (P5091) significantly increased tau polyubiquitination”
“we added DMSO or USP7 inhibitor (P5019, 10 μΜ) to cells 6 hours before transfection”
RNF140 replaces RNF149 in the IP/MS description
MinorThe IP/MS sample-collection sentence names RNF140, but the reported interactors from that effort are for RNF149.
“we collected affinity-purified RNF130- and RNF140-interacting proteins by immunoprecipitation in 293T cells”
“This effort identified 288 putative interactors for RNF130 and 413 for RNF149”
Table S5 is cited for the wrong analysis
MinorThe results cite Table S5 for validation of 11 tau regulators in mouse brains, but the supplemental listing identifies Table S5 as the RNF130/RNF149 IP/MS analysis.
“The IB analysis of brain homogenates from the injected mice revealed that KD of the 11 candidate tau regulators significantly reduced endogenous tau levels by at least 15% (Figures 1E and 1F; Table S5).”
“Table S5. RNF130/RNF149 associators from IP/MS analysis, related to Figure 4”
Table S6 is cited for the wrong analysis
MinorThe results cite Table S6 for RNF130/RNF149 interactors, but the supplemental listing identifies Table S6 as the genes and shRNAs tested for in vivo validation.
“This effort identified 288 putative interactors for RNF130 and 413 for RNF149, with 185 of the interactors overlapping (Figure 4A; Table S6).”
“Table S6. shRNAs and target genes tested for in vivo validation, related to Figure 1”
Validated regulator count differs by one
MinorThe introduction reports 82 validated regulators, whereas the summary and results report 83 validated hits.
“We identified and validated 82 regulators of tau protein levels”
“From this validation, 83 hits showed significantly altered tau levels upon genetic KD”
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Metadata
- Authors
- Kim, J., de Haro, M., Al-Ramahi, I., Garaicoechea, L. L., Jeong, H.-H., Sonn, J. Y., Tadros, B., Liu, Z., Botas, J., & Zoghbi, H. Y.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zoghbi, Huda Yahya
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 111
- Issue
- 6
- Pages
- 824-838.e7
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W4313641681
- Cited by
- 50
- References
- 48
- Citations by year
- 2026: 14 · 2025: 12 · 2024: 16 · 2023: 8
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tauopathy, Alzheimer's disease, corticobasal degeneration, chronic traumatic encephalopathy, CHIP, Hsc70-interacting protein, USP7, Drosophila, mouse model, therapeutic target, E3 ubiquitin ligase
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Adult, Alzheimer Disease, Animals, Brain, Drosophila, Humans, tau Proteins, Tauopathies, Mice
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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.
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