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Cited by 283Alzheimer's disease research and treatmentsProtein Degradation and InhibitorsDementia and Cognitive Impairment Research

Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

Open access
Silva, M Catarina, Ferguson, Fleur M, Cai, Quan, Donovan, Katherine A, Nandi, Ghata, Patnaik, Debasis, Zhang, Tinghu, Huang, Hai-Tsang +6 more·2019·eLife
DOI 10.7554/elife.45457PMC PMC6450673
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Abstract

Tauopathies are neurodegenerative diseases characterized by aberrant forms of tau protein accumulation leading to neuronal death in focal brain areas. Positron emission tomography (PET) tracers that bind to pathological tau are used in diagnosis, but there are no current therapies to eliminate these tau species. We employed targeted protein degradation technology to convert a tau PET-probe into a functional degrader of pathogenic tau. The hetero-bifunctional molecule QC-01–175 was designed to engage both tau and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, to trigger tau ubiquitination and proteasomal degradation. QC-01–175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, with minimal effect on tau from neurons of healthy controls, indicating specificity for disease-relevant forms. QC-01–175 also rescued stress vulnerability in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.

AI snapshot

Written from the paper’s full text.

TL;DR

QC-01–175 is a hetero-bifunctional tau degrader derived from the tau PET tracer T807 and the CRBN ligand pomalidomide that clears disease-relevant tau species in FTD patient-derived neurons. It acts via CRL4CRBN and the proteasome, spares tau in healthy control neurons, and rescues Aβ(1–42)-induced stress vulnerability.

Key findings

  • QC-01–175 bound recombinant tau WT (KD 1.2 μM), A152T (KD 1.7 μM), and P301L (KD 2.5 μM) within the same order of magnitude as T807 (KD 1.8, 2.1, and 1.7 μM, respectively), and showed reduced MAO inhibition relative to T807 (IC50 8.56 μM vs 0.14 μM).
  • In FTD patient-derived neurons, QC-01–175 caused concentration-dependent tau clearance: A152T neurons showed Dmax,24h of 75% for total tau and 85% for P-tauS396; P301L neurons showed Dmax,24h of 60% for both tau species at 1 μM, with western blotting showing 70% total tau and 80% P-tauS396 reduction at 1 μM.
  • The inactive control QC-03–075 had minimal or no effect on tau levels, and QC-01–175 had minimal effect on tau in three non-affected control neuronal lines up to 1 μM; at 10 μM it induced ~20% total tau degradation in two control lines and ~40% P-tauS396 degradation in one control line.
  • Mechanism studies showed rescue by excess lenalidomide or T807, by the NAE inhibitor MLN4924, and by the proteasome inhibitor carfilzomib, but not by the autophagy inhibitor bafilomycin A1; co-IP supported ternary complex formation, and proteomics identified >8000 proteins with only ZFP91, ZNF653, and ZNF827 as significant off-target changes.
  • QC-01–175 pre-treatment rescued Aβ(1–42)-induced viability loss in A152T neurons to 90% of vehicle-alone control, compared with 50% viability loss in vehicle-pretreated neurons and 100% rescue in MAPT-knockout neurons.

Methods

  • The study designed and synthesized a 25-member library of hetero-bifunctional tau degraders based on T807, a linker, and pomalidomide, identifying QC-01–175 and the negative control QC-03–075.
  • Binding was measured by biolayer interferometry against recombinant human tau WT, A152T, and P301L; MAO activity was measured with a MAO-Glo assay.
  • Human iPSC-derived cortical-enriched NPCs from A152T, P301L, and non-mutant control lines were differentiated into neurons for 6–8 weeks and analyzed by tau ELISA, western blotting, immunofluorescence, co-IP, TMT mass-spectrometry proteomics, and AlamarBlue viability assays.

Limitations

  • The paper states that E. coli-expressed recombinant tau has properties not reflective of intracellular tau conformations, limiting in vitro binding measurements; it also notes variability in degradation across biological replicates and that proteasome function may be affected by neurodegeneration and aging.
  • The paper states that QC-01–175 is relatively large and flexible, may suffer from fast metabolism and poor brain penetration, and that off-target C2H2 zinc finger degradation and other possible off-target binding require further evaluation; tau could not be reliably quantified by proteomics.
  • Evident from the text: the study is limited to two FTD tau variants (A152T and P301L) in iPSC-derived neuronal models, with no in vivo animal efficacy or human clinical data reported.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.7554/elife.45457

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 51 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Immunoprecipitation of tau showed co-IP with CRBN in QC-01-175 treated samples ± carfilzomib or bortezomib.

    “Conversely, immunoprecipitation of tau (TAU5 antibody) and western blotting analysis showed co-IP with CRBN in QC-01–175 treated samples ± carfilzomib or bortezomib”
    Quote in the paperSubstantial claim
  • Findingcitation

    QC-01-175 and T807 displayed significantly lower affinity for recombinant immobilized tau forms than the reported KD of T807 for native, aggregated tau filaments from AD brain sections (KD 15 nM).

    “As expected, in vitro QC-01–175 and T807 displayed a significantly lower affinity for all recombinant immobilized tau forms than the reported KD of T807 for native, aggregated tau filaments from AD brain sections (KD15 nM)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chien et al., 2013 source

      Not checked in the free run.

    • cites Gobbi et al., 2017 source

      Not checked in the free run.

    • cites Xia et al., 2013 source

      Not checked in the free run.

  • Findingcitation

    Aβ(1-42) proteotoxicity promotes concentration-dependent loss of viability in A152T and P301L neurons.

    “One of these stressors is the proteotoxicity caused by the highly aggregation-prone peptide Aβ(1-42), which promotes a concentration-dependent loss of viability in A152T and P301L neurons”
    Quote in the paperSubstantial claim
  • Findingown data

    QC-01-175 had minimal effect on tau from neurons of healthy controls.

    “with minimal effect on tau from neurons of healthy controls”
    • Also stated in: § QC-01–175 preferentially degrades tau species found in FTD neurons vs. healthy controls · plain
      “No significant degradation of tau or P-tauS396 was observed after 24 hr treatment with either QC-01–175 or negative control QC-03–075 at concentrations up to 1 μM in all three control neurons”
    Quote in the paperSubstantial claim
  • Findingown data

    QC-01-175 effected clearance of tau in FTD patient-derived neuronal cell models.

    “QC-01–175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models”
    • Also stated in: § QC-01–175 promotes tau clearance in a human neuronal cell model of tauopathy · boosted
      “Collectively, these results demonstrate that QC-01–175 targets multiple forms of tau for degradation in FTD neuronal cell models.”
    Quote in the paperSubstantial claim
  • May combine two claims. 40
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    In P301L neurons, 24 hr treatment with 1 μM QC-01-175 resulted in 70% reduction in total tau and 80% reduction of P-tauS396 by western blotting.

    “24 hr treatment with 1 μM QC-01–175 resulted in a 70% reduction in total tau and an 80% reduction of P-tauS396”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In P301L neurons by 8 hr, robust degradation of tau and P-tauS396 (40-50%) was achieved at all concentrations above 500 nM, and Dmax, 8h was further increased to 60-70% by 24 hr.

    “However, by 8 hr robust degradation of tau and P-tauS396(40–50%) was achieved at all concentrations above 500 nM, and Dmax, 8h was further increased to 60–70% by 24 hr”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In P301L neurons at 4 hr, there was more variability between the two tau species.

    “In P310L neurons, there was more variability between the two tau species at the 4 hr time-point”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Negative control QC-03-075 (1 μM) revealed no effect on these proteins, confirming ablation of CRBN-binding activity.

    “Conversely, the negative control QC-03–075 (1 μM) revealed no effect on these proteins, confirming the ablation of CRBN-binding activity”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In tau-P301L neurons, QC-01-175 effected concentration-dependent degradation of total and P-tauS396 at 24 hr, with Dmax, 24h of 60% achieved at 1 μM for both tau species.

    “QC-01–175 effected concentration-dependent degradation of total and P-tauS396 at the 24 hr time point, with a Dmax, 24h of 60% achieved at 1 μM compound for both tau species”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 10 μM, QC-01-175 induced ~20% degradation of total tau in two of the control lines (1 and 2) and had no effect in the third line.

    “At the highest dose of 10 μM, QC-01–175 induced ~20% degradation of total tau in two of the control lines (1 and 2) and had no effect in the third line.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Probing with ubiquitin antibody showed increase in ubiquitinated proteins by QC-01-175 ± carfilzomib treatment, with same migration as tau (~50 kDa), consistent with QC-01-175-mediated increase in tau ubiquitination.

    “Probing with an ubiquitin antibody (W:Ubi-1, Figure 4A) showed an increase in ubiquitinated proteins by QC-01–175 ± carfilzomib treatment, with the same migration as tau (~50 kDa), consistent with a QC-01–175-mediated increase in tau ubiquitination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The observed Dmax, 24h was 75% for total tau and 85% for P-tau S396, averaged across independent replicates.

    “The observed Dmax, 24h of 75% for total tau and of 85% for P-tau S396, averaged across independent replicates”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Autophagy inhibitor bafilomycin A1 did not reverse the degrader effect and further promoted tau clearance.

    “In contrast, the autophagy inhibitor bafilomycin A1 (Baf.A1) did not reverse the degrader effect and further promoted tau clearance”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    QC-01-175 promoted between 50 and 100% tau clearance, a statistically significant reduction relative to vehicle.

    “QC-01–175 promoted between 50 and 100% tau clearance, a statistically significant reduction relative to vehicle”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 10 μM, QC-01-175 degraded ~40% of P-tauS396 in control line 1 and had no significant effect in control lines 2 and 3.

    “Similarly, 10 μM QC-01–175 degraded ~40% of P-tauS396 in control line 1 and had no significant effect in control lines 2 and 3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In P301L neurons at 4 hr, total tau showed hook effect with Dmax at 100 nM, whereas P-tauS396 maximal degradation at 500 nM (both Dmax, 4h = 80%).

    “For total tau, we observed a hook effect with Dmax, 4h occurring at 100 nM, whereas for P-tauS396 maximal degradation was observed at 500 nM (both Dmax, 4h = 80%)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Upon 4 hr treatment with 1 μM QC-01-175, the only significant changes observed comprise validated IMiD targets ZFP91, ZNF653 and ZNF827, while no QC-01-175 specific off-targets were observed.

    “Upon 4 hr treatment with 1 μM QC-01–175, the only significant changes observed comprise the validated immune-modulatory drug (IMiD) targets ZFP91, ZNF653 and ZNF827 (Donovan et al., 2018), while no QC-01–175 specific off-targets were observed”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In A152T neurons at 4 hr, QC-01-175 produced constant 50% degradation at 500 nM and 1 μM and little effect at 10 μM.

    “constant 50% degradation at 500 nM and 1 μM (Figure 5C), and little effect on tau levels at 10 μM QC-01–175”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    QC-01-175 and T807 show micromolar affinities to immobilized, soluble recombinant tau protein, independent of the presence of a tau variant.

    “Despite detecting binding, QC-01–175 and T807 showed micromolar affinities to immobilized, soluble protein, independent of the presence of a tau variant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    QC-01-175 can recognize and downregulate other proteins.

    “The degrader can recognize and downregulate other proteins as shown here by mass spectrometry global proteome analysis (Figure 6A)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    QC-01-175 preferentially targets tau species from FTD neurons, with minimal effect on tau from unaffected WT control neurons.

    “Remarkably, the degrader preferentially targeted tau species from FTD neurons, with minimal effect on tau from unaffected WT control neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    This effect on viability is not seen in WT control neurons and can be rescued by CRISPR/Cas9-mediated MAPT knockout in A152T neurons.

    “This effect on viability is not seen in WT control neurons and can be rescued by CRISPR/Cas9-mediated MAPT knockout (KO) in A152T neurons”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Silva et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early tau post-translational modifications lead to misfolding, mislocalization, oligomerization, and changes in solubility, and these events appear to be determinant toxicity effectors.

    “Cumulative evidence from murine tauopathy models and postmortem patient brain studies suggests that early tau post-translational modifications lead to misfolding, mislocalization, oligomerization, and changes in solubility. These events appear to be determinant toxicity effectors”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Johnson and Stoothoff, 2004

      Not checked in the free run.

    • cites Min et al., 2015 source

      Not checked in the free run.

    • cites Wang et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    18F-T807 binds P-tau in vivo in a conformation-dependent manner, with highest efficiency in MAPT mutation carriers that produce AD-like PHF pathology, showing increased uptake in brain regions with significant tau deposition burden and little background binding in the cortex of normal brains.

    “18F-T807 binds P-tau in vivo in a conformation-dependent manner, with highest efficiency in MAPT mutation carriers that produce AD-like PHF pathology (Jones et al., 2018), showing increased uptake in brain regions with significant tau deposition burden and little background binding in the cortex of normal brains.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Jones et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Targeting early forms of toxic tau for clearance may facilitate the study of their role in disease etiology and be a promising therapeutic strategy to reduce neuronal degeneration.

    “Therefore, targeting early forms of toxic tau for clearance may facilitate the study of their role in disease etiology and be a promising therapeutic strategy to reduce neuronal degeneration.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Anti-tau immunotherapy has shown promise in animal models, but antibody affinity and specificity as well as strong immune responses pose critical challenges.

    “Moreover, anti-tau immunotherapy has shown promise in animal models, but antibody affinity and specificity as well as strong immune responses pose critical challenges”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gu et al., 2013

      Not checked in the free run.

    • cites Panza et al., 2016 source

      Not checked in the free run.

    • cites Pedersen and Sigurdsson, 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Tauopathies are neurodegenerative diseases characterized by pathological accumulation of hyper-phosphorylated tau in paired helical filaments or neurofibrillary tangles within neurons and glia of affected brain regions, leading to cell death.

    “Tauopathies are neurodegenerative diseases characterized by aberrant forms of tau protein accumulation leading to neuronal death in focal brain areas.”
    • Also stated in: § Introduction · plain
      “Tauopathies, such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD), are a group of neurodegenerative diseases characterized by the pathological accumulation of hyper-phosphorylated tau (P-tau) protein, in the form of intracellular paired helical filaments (PHFs) or neurofibrillary tangles (NFTs), within neurons and glia of affected brain regions,”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kosik et al., 1989 source

      Not checked in the free run.

    • cites Morris et al., 2011 source

      Not checked in the free run.

    • cites Cruts and Van Broeckhoven, 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Targeted protein degraders, also known as PROTACs, are an emerging strategy for ablating previously undruggable protein functions.

    “Targeted protein degraders, also known as PROTACs (PROteolysis TArgeting Chimeras), are an emerging strategy for ablating previously undruggable protein functions”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cromm et al., 2018 source

      Not checked in the free run.

    • cites Gechijian et al., 2018 source

      Not checked in the free run.

    • cites Xie et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Targeted protein degradation approaches have expanded the landscape of druggable proteins by providing a mechanism to transform a non-functional protein binder into an effective targeted degrader.

    “Targeted protein degradation approaches have expanded the landscape of druggable proteins by providing a mechanism to transform a non-functional protein binder into an effective targeted degrader”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gechijian et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    18F-T807 is the most advanced tau PET tracer in terms of its investigation in vivo, with studies completed in numerous tauopathies including AD and PSP.

    “18F-T807 is the most advanced tau PET tracer in terms of its investigation in vivo, with studies completed in numerous tauopathies including AD and PSP”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Holt et al., 2016 source

      Not checked in the free run.

    • cites Jones et al., 2018 source

      Not checked in the free run.

    • cites Murugan et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In vitro testing suggests QC-01-175 has preserved tau ligand-binding capacity and reduced off-target MAO inhibition.

    “Together, in vitro testing of QC-01–175 suggests that it has a preserved tau ligand-binding capacity and reduced off-target MAO inhibition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Both variant and WT forms of tau are recognized and degraded by QC-01-175.

    “indicating that both variant and WT forms of tau are recognized and degraded”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patient-specific cellular models express tau at endogenous levels and recapitulate disease-relevant tau phenotypes ex vivo.

    “These patient-specific cellular models that express tau at endogenous levels, recapitulate disease-relevant tau phenotypes ex vivo”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fong et al., 2013 source

      Not checked in the free run.

    • cites Silva et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These results support ternary complex formation between tau, degrader and CRL4CRBN followed by increased tau ubiquitination at 4 hr.

    “These results support ternary complex formation between tau, degrader and CRL4CRBN followed by increased tau ubiquitination, at the 4 hr time point”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.

    “This work demonstrates that aberrant tau in FTD patient-derived neurons is amenable to targeted degradation, representing an important advance for therapeutics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    QC-01-175-mediated tau degradation is dependent on CRBN and tau binding, neddylation (E3 ligase function) and proteasome function, but not autophagy.

    “Taken together, these data establish that QC-01–175-mediated tau degradation is dependent on CRBN and tau binding, neddylation (E3 ligase function) and proteasome function, but not autophagy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CRBN inhibition alone may lead to accumulation of P-tau in A152T neurons, which are more sensitive to modulators of the proteasome than healthy neurons.

    “indicating that CRBN inhibition alone may lead to accumulation of P-tau in these neurons, which are more sensitive to modulators of the proteasome than healthy neurons”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Silva et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    For T807 and QC-01-175, the values of 'Response' and Req match as evidenced by the raw data as well as a value of Rmax/Req (%) close to 1.

    “For T807 and QC-01–175, the values of ‘Response’ and Req match as evidenced by the raw data as well as a value of Rmax/Req (%) close to 1.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    QC-01-175 is a relatively large and flexible molecule compared to most brain-active drugs and may suffer from fast metabolism and poor brain penetration.

    “From a pharmacology standpoint, QC-01–175 is a relatively large and flexible molecule compared to most brain-active drugs and may suffer from fast metabolism and poor brain penetration.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cell lines' identity was authenticated by SANGER sequencing, karyotyping and ACGH analysis at different stages of culture maintenance from iPSC to NPC.

    “Cell lines’ identity was authenticated by SANGER sequencing, karyotyping and ACGH analysis at different stages of culture maintenance from iPSC to NPC.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    The impact of proteostasis on UPS function does not preclude the development of targeted degraders as therapeutic strategies for early stage disease, or as a co-therapeutic with proteasome activity chemical enhancers.

    “This, however, does not preclude the development of targeted degraders as therapeutic strategies for early stage disease, or as a co-therapeutic with proteasome activity chemical enhancers (Myeku and Duff, 2018).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Myeku and Duff, 2018

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    In conclusion, tau degrader QC-01-175 triggers proteasome-dependent tau and P-tau clearance in FTD patient-derived neurons, which is able to rescue tau-mediated toxicity in biologically relevant assays of stress vulnerability.

    “In conclusion, the tau degrader QC-01–175 triggers proteasome-dependent tau and P-tau clearance in FTD patient-derived neurons, which is able to rescue tau-mediated toxicity in biologically relevant assays of stress vulnerability.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Human stem cell-derived neurons allow access to physiologically relevant cell types and protein complexes, offering the advantage of modeling pathogenic tau species without the need for overexpression of heterologous genes, in the context of the patient genomic background.

    “Human stem cell-derived neurons allow access to physiologically relevant cell types and protein complexes, offering the advantage of modeling pathogenic tau species without the need for overexpression of heterologous genes, in the context of the patient genomic background”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Dolmetsch and Geschwind, 2011

      Not checked in the free run.

    • cites Silva et al., 2017 source

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    • cites Wan et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All working cell lines tested negative for mycoplasma contamination.

    “All working cell lines tested negative for mycoplasma contamination.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    If all curves have reached equilibrium, the values of 'Response' and Req should match.

    “As per the instrument manufacturer’s instructions, if all curves have reached equilibrium, these two sets of values correspond to ‘Response,’ and Req values should match.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites instrument manufacturer’s instructions

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Proteome Discoverer 2.2 was used for .RAW file processing and to control peptide and protein level false discovery rates, assemble proteins from peptides, and quantify protein from peptides.

    “Proteome Discoverer 2.2 (ThermoFisher Scientific) was used for .RAW file processing and controlling peptide and protein level false discovery rates, assembling proteins from peptides, and protein quantification from peptides.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pomalidomide has been reported to induce degradation of multiple members of the C2H2 zinc finger protein family through a 'molecular glue' type mechanism.

    “which has been reported to induce degradation of multiple members of the C2H2 zinc finger protein family through a ‘molecular glue’ type mechanism (Sievers et al., 2018)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sievers et al., 2018 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Small-molecule-mediated protein degradation represents a promising strategy to advance understanding of human neurodegenerative disease and translate those insights into targeted therapies.

    “our study suggests that small-molecule-mediated protein degradation represents a promising strategy to advance our understanding of human neurodegenerative disease and translate those insights into targeted therapies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Tau could be a natural substrate of CRBN through a complex involving the amyloid precursor protein (APP), mutations in which are known to cause AD.

    “Del Prete et al. reported that tau could be a natural substrate of CRBN through a complex involving the amyloid precursor protein (APP), mutations in which are known to cause AD (Del Prete et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Del Prete et al., 2016 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    MS/MS spectra were searched against a Uniprot human database (September 2016) containing both the forward and reverse sequences.

    “MS/MS spectra were searched against a Uniprot human database (September 2016) with both the forward and reverse sequences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Variation in QC-01-175-mediated tau degradation dose profiles between A152T and P301L neurons possibly also points to differences in proteostasis for the two patient-derived cell models, which affects UPS function.

    “and possibly also differences in proteostasis for the two patient-derived cell models, which affects UPS function”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Approval for human subjects' work was obtained under a Partners/MGH-approved IRB Protocol (#2010P001611/MGH).

    “Approval for human subjects’ work was obtained under a Partners/MGH-approved IRB Protocol (#2010P001611/MGH).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Purities of assayed compounds were in all cases greater than 95%, as determined by reverse-phase HPLC analysis.

    “Purities of assayed compounds were in all cases greater than 95%, as determined by reverse-phase HPLC analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    In the LC-MS data analysis, peptide spectral matches with poor quality MS3 spectra (summed signal-to-noise across 11 channels < 200 and precursor isolation specificity < 0.5) were excluded from quantitation, and the resulting data were filtered to include only proteins with a minimum of two unique peptides identified.

    “Peptide spectral matches with poor quality MS3 spectra were excluded from quantitation (summed signal-to-noise across 11 channels < 200 and precursor isolation specificity < 0.5), and resulting data was filtered to only include proteins that had a minimum of two unique peptides identified.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Because degraders can act catalytically, their pharmacodynamics may influence and complicate PET readings.

    “However, because degraders can act catalytically, their pharmacodynamics may influence and complicate PET readings.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Degraders can act catalytically.

  • May combine two claims.

    Interpretationreasoning

    Current heterologous cell culture systems and in vitro measurements do not recapitulate endogenous cellular tau properties.

    “This is a limitation of current heterologous cell culture systems and in vitro measurements that do not recapitulate endogenous cellular tau properties.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Since QC-01-175 occupies the binding site of a PET ligand, it might be possible to use PET to measure target engagement in vivo.

    “Since QC-01–175 occupies the binding site of a PET ligand, it might be possible to use PET to measure target engagement in vivo.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: QC-01–175 occupies the binding site of a PET ligand.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    QC-01-175 promoting efficacy of a physiological process increases the probability of successful tau degradation in vivo.

    “increasing the probability of successful tau degradation in vivo”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The approach may be generalizable to other proteinopathies where high-quality PET tracers and cellular models are available.

    “Importantly, our approach may be generalizable to other proteinopathies where high-quality PET tracers and cellular models are available.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    QC-01-175 may also have a modulatory effect on function/activity of other proteins without leading to degradation.

    “However, QC-01–175 may also have modulatory effect on function/activity of other proteins without leading to degradation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    It may be possible to develop tau-degrader therapies that selectively act in FTD-affected neurons, and on disease-associated forms of tau, independent of genotype, and spare normal tau protein within the affected regions of the brain.

    “This indicates that it may be possible to develop tau-degrader therapies that selectively act in FTD-affected neurons, and on disease-associated forms of tau, independent of genotype, and spare normal tau protein within the affected regions of the brain.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The instrument manufacturer recommends the steady state option for analyzing interactions that are either low affinity or very fast on-and-off affinity rates.

    “The instrument manufacturer (Fortebio, article #137) recommends the steady state option for analyzing interactions that are either low affinity or very fast on-and-off affinity rates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fortebio, article #137

      Not checked in the free run.

58 of 58

  • The paper relies on this without support.

    There are currently no effective disease-modifying therapies for tauopathies or FTD.

    “Despite its devastating effects, there are currently no effective disease-modifying therapies, highlighting an urgent unmet need.”
    “there are no current therapies to eliminate these tau species”

  • The paper relies on this without support.

    There is a lack of a well-defined tau fold and active sites in disease.

    “A challenge in developing cell-permeable small molecules that target tau is the lack of a well-defined tau fold and active sites, in disease.”

  • The authors state this as an assumption.

    Maximum engagement of QC-01–175 with tau and CRL4CRBN would be captured within a shorter interval (4 hr).

    “We performed this experiment upon 4 hr of 1 μM QC-01–175 treatment, under the assumption that maximum engagement would be captured within a shorter interval.”

  • The paper relies on this without support.

    QC-01–175 occupies the binding site of a PET ligand.

    “Since QC-01–175 occupies the binding site of a PET ligand”

  • The paper relies on this without support.

    Degraders can act catalytically.

    “because degraders can act catalytically”
5 of 5

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?

  • TPD may expand the ability to target the remaining 80% of the human proteome previously considered undruggable by utilizing phenotypically silent ligands as POI-recruiting handles.

    “Finally TPD may expand our ability to target the remaining 80% of the human proteome that has previously been considered undruggable (Russ and Lampel, 2005), due to the ability to utilize phenotypically silent ligands as POI-recruiting handles (Silva et al., 2019).”

    From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Silva et al., 2019

  • One strategy has utilized such PET tracers by turning them into tool PROTAC molecules that target tau by recruiting CRBN, and these were shown to cause degradation of tau species in cell-based models of tauopathy.

    “In fact, one strategy has utilized such PET tracers by turning them into tool PROTAC molecules that target tau by recruiting CRBN, and these were shown to cause degradation of tau species in cell-based models of tauopathy191.”

    From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [191]

  • Target degradation rather than inhibition is a promising therapeutic modality for diseases driven by the accumulation of aberrant forms of proteins, such as tauopathies.

    “Finally, target degradation rather than inhibition is a promising therapeutic modality for diseases driven by the accumulation of aberrant forms of proteins, such as tauopathies 32 .”

    From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [32]

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.

  • Same chemical formula is assigned two different expected masses

    Minor

    The formula C30H32N2O3Si is assigned an expected mass of 464.23 Da for compound 5 but 496.68 Da for compound 4. The same formula cannot have both masses.

  • Figure 3 gives conflicting QC-01-175 treatment durations

    Minor

    The Results describe 24 hours of QC-01-175 treatment with a separate 6-hour inhibitor pre-treatment. The Figure 3 caption instead specifies 18 hours of QC-01-175 treatment and 24 hours total.

2 of 2

The citation lists haven’t been fetched yet

References 100 · Cited by 283

Research works printed but not linked: 1

  1. Neumann, 2015, Hodges' Frontotemporal Dementia, 165

Authors
Silva, M. C., Ferguson, F. M., Cai, Q., Donovan, K. A., Nandi, G., Patnaik, D., Zhang, T., Huang, H.-T., Lucente, D. E., Dickerson, B. C., Mitchison, T. J., Fischer, E. S., Gray, N. S., & Haggarty, S. J.
Affiliations
  • Harvard University (US)
  • Dana-Farber Cancer Institute (US)
Corresponding author
  • Gray, Nathanael S
  • Haggarty, Stephen J
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2019-03-25
Volume
8
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.45457
PMC
PMC6450673
OpenAlex
W2924474406
Cited by
283
References
100
Citations by year
2026: 35 · 2025: 31 · 2024: 32 · 2023: 35 · 2022: 39 · 2021: 45 · 2020: 51 · 2019: 15
FWCI
25.71
Type
journal article
Language
en
Update notices
correction (2026-10-23)
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R21NS085487, R01CA214608, R01CA218278)
  • Tau Consortium
  • F-Prime Biomedical Research Initiative
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tauopathy, frontotemporal dementia, targeted protein degradation, cereblon, ubiquitination, proteasomal degradation, tau PET tracers, patient-derived neurons, stress vulnerability, tau clearance
MeSH terms
Cell Line, Humans, Models, Theoretical, Neurons, tau Proteins, Neuroprotective Agents, Tauopathies, Frontotemporal Dementia, Proteolysis

About these checks

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 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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