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

  1. M Catarina Silva
  2. Fleur M Ferguson
  3. Quan Cai
  4. Katherine A Donovan
  5. Ghata Nandi
  6. Debasis Patnaik
  7. Tinghu Zhang
  8. Hai-Tsang Huang
  9. Diane E Lucente
  10. Bradford C Dickerson
  11. Timothy J Mitchison
  12. Eric S Fischer
  13. Nathanael S Gray  Is a corresponding author
  14. Stephen J Haggarty  Is a corresponding author
  1. Massachusetts General Hospital, Harvard Medical School, United States
  2. Dana-Farber Cancer Institute, United States
  3. Harvard Medical School, United States

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.

Data availability

Mass spectrometry global proteomics data is available via the PRIDE archive, under the project accession number PXD012515. Source data files have been provided for Figures 2, 5 and 7.

The following data sets were generated

Article and author information

Author details

  1. M Catarina Silva

    Chemical Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    M Catarina Silva, is a co-inventor on a patent covering the molecules disclosed in this publication (WO/2019/014429).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5421-6673
  2. Fleur M Ferguson

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Fleur M Ferguson, is a co-inventor on a patent covering the molecules disclosed in this publication (WO/2019/014429).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4091-7617
  3. Quan Cai

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Quan Cai, is a co-inventor on a patent covering the molecules disclosed in this publication (WO/2019/014429).
  4. Katherine A Donovan

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Ghata Nandi

    Chemical Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Debasis Patnaik

    Chemical Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  7. Tinghu Zhang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Hai-Tsang Huang

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4244-2304
  9. Diane E Lucente

    Molecular Neurogenetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  10. Bradford C Dickerson

    MGH Frontotemporal Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    Bradford C Dickerson, is a consultant for Merck, Lilly, Biogen, and Piramal; and receives royalties from Oxford University Press, Cambridge University Press, and Elsevier.
  11. Timothy J Mitchison

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  12. Eric S Fischer

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    Competing interests
    Eric S Fischer, is a SAB member and equity holder in C4 Therapeutics and a consultant to Novartis, AbbVie, and Pfizer. The Fischer lab receives or has received research funding from Novartis, Astellas and Deerfield.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7337-6306
  13. Nathanael S Gray

    Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States
    For correspondence
    nathanael_gray@dfci.harvard.edu
    Competing interests
    Nathanael S Gray, is a founder, science advisory board member (SAB) and equity holder in Gatekeeper, Syros, Petra, C4, B2S and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Her2llc, Deerfield and Sanofi. Co-inventor on a patent covering the molecules disclosed in this publication (WO/2019/014429).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5354-7403
  14. Stephen J Haggarty

    Chemical Neurobiology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    For correspondence
    shaggarty@mgh.harvard.edu
    Competing interests
    Stephen J Haggarty, is a member of the SAB and equity holder in Rodin Therapeutics, Psy Therapeutics, and Frequency Therapeutics. His laboratory has received funding from the Tau Consortium, F-Prime Biomedical Research Initiative, AstraZeneca, JW Pharmaceuticals and speaking fees from AstraZeneca, Amgen, Merck. Co-inventor on a patent covering the molecules disclosed in this publication (WO/2019/014429).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7872-168X

Funding

National Institutes of Health (R21NS085487)

  • M Catarina Silva
  • Diane E Lucente
  • Bradford C Dickerson
  • Stephen J Haggarty

Tau Consortium

  • M Catarina Silva
  • Ghata Nandi
  • Debasis Patnaik
  • Stephen J Haggarty

F-Prime Biomedical Research Initiative

  • M Catarina Silva
  • Fleur M Ferguson
  • Ghata Nandi
  • Debasis Patnaik
  • Nathanael S Gray
  • Stephen J Haggarty

National Institutes of Health (R01CA214608)

  • Katherine A Donovan
  • Eric S Fischer

National Institutes of Health (R01CA218278)

  • Katherine A Donovan
  • Eric S Fischer

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.Eric S Fischer is a Damon Runyon-Rachleff Innovator supported in part by the Damon Runyon Cancer Research Foundation (DRR-50-18).

Reviewing Editor

  1. Benjamin F Cravatt, The Scripps Research Institute, United States

Version history

  1. Received: January 23, 2019
  2. Accepted: March 23, 2019
  3. Accepted Manuscript published: March 25, 2019 (version 1)
  4. Version of Record published: April 5, 2019 (version 2)

Copyright

© 2019, Silva et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. M Catarina Silva
  2. Fleur M Ferguson
  3. Quan Cai
  4. Katherine A Donovan
  5. Ghata Nandi
  6. Debasis Patnaik
  7. Tinghu Zhang
  8. Hai-Tsang Huang
  9. Diane E Lucente
  10. Bradford C Dickerson
  11. Timothy J Mitchison
  12. Eric S Fischer
  13. Nathanael S Gray
  14. Stephen J Haggarty
(2019)
Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
eLife 8:e45457.
https://doi.org/10.7554/eLife.45457

Share this article

https://doi.org/10.7554/eLife.45457

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