PXD012515 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Targeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-Derived Neuronal Cell Models |
Description | Tauopathies are a family of neurodegenerative diseases characterized by a shared pathology of aberrant forms of tau protein accumulation leading to neuronal death in focal areas of the brain. Positron emission tomography (PET) tracers that bind to tau aggregates are used to aid 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 Cullin-4 RING E3 ubiquitin ligase family member (CRL4CRBN), to trigger tau ubiquitination and proteasomal degradation. QC-01-175 effected clearance of tau in frontotemporal dementia (FTD) patient-derived neuronal cell models, which recapitulate disease phenotypes of tau accumulation, insolubility and toxicity. Furthermore, QC-01-175 had minimal effect on tau levels in neurons from healthy controls, indicating specificity for degradation of disease-relevant forms of tau. QC-01-175 also rescued vulnerability to stress in FTD neurons, phenocopying CRISPR-mediated MAPT-knockout. This work demonstrates that aberrant tau species formed in ex vivo FTD patient-derived neurons are amenable to targeted protein degradation, representing an important advance towards the development of a tau targeted therapeutic. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_04:52:44.419.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Eric Fischer |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2019-01-25 07:40:34 | ID requested | |
1 | 2019-03-26 04:57:28 | announced | |
⏵ 2 | 2024-10-22 04:52:52 | announced | 2024-10-22: Updated project metadata. |
Publication List
Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT, Lucente DE, Dickerson BC, Mitchison TJ, Fischer ES, Gray NS, Haggarty SJ, Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife, 8():(2019) [pubmed] |
10.7554/elife.45457; |
Keyword List
curator keyword: Biomedical |
submitter keyword: crl4,Tau, CRBN, Frontotemporal dementia, PROTAC, ubiquitin |
Contact List
Eric Fischer |
contact affiliation | Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA |
contact email | eric_fischer@dfci.harvard.edu |
lab head | |
Eric Fischer |
contact affiliation | Dana-Farber Cancer Institute |
contact email | eric_fischer@dfci.harvard.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD012515
- Label: PRIDE project
- Name: Targeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-Derived Neuronal Cell Models