2. Academic Validation
  3. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models

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

  • Elife. 2019 Mar 25;8:e45457. doi: 10.7554/eLife.45457.
M Catarina Silva  # 1 2 3,  Fleur M Ferguson  # 4 5,  Quan Cai 4 5,  Katherine A Donovan 4 5,  Ghata Nandi 1 2 3,  Debasis Patnaik 1 2 3,  Tinghu Zhang 4 5,  Hai-Tsang Huang 4 5,  Diane E Lucente 6 7 8 9,  Bradford C Dickerson 7 8 9,  Timothy J Mitchison 10 11,  Eric S Fischer 4 5,  Nathanael S Gray 4,  Stephen J Haggarty 1 2 3
Affiliations

Affiliations

  • 1 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
  • 2 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
  • 3 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, United States.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
  • 6 Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
  • 7 MGH Frontotemporal Disorders Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
  • 8 Gerontology Research Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
  • 9 Alzheimer's Disease Research Center, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, United States.
  • 10 Department of Systems Biology, Harvard Medical School, Boston, United States.
  • 11 Laboratory of Systems Pharmacology, Harvard Medical School, Boston, United States.
  • # Contributed equally.
PMID: 30907729 DOI: 10.7554/eLife.45457
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.

Keywords

biochemistry; chemical biology; degrader; frontotemporal dementia; human; human neuronal cell models; neuroscience; tau.

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