Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
- Massachusetts General Hospital, Harvard Medical School, United States
- Dana-Farber Cancer Institute, United States
- 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.
Article and author information
Author details
Stephen J Haggarty
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).
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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Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models
eLife 8:e45457.
https://doi.org/10.7554/eLife.45457
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