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PXD012515

PXD012515 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleTargeted Degradation of Aberrant Tau in Frontotemporal Dementia Patient-Derived Neuronal Cell Models
DescriptionTauopathies 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_04:52:44.419.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterEric Fischer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListTMT6plex-126 reporter+balance reagent acylated residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02019-01-25 07:40:34ID requested
12019-03-26 04:57:28announced
22024-10-22 04:52:52announced2024-10-22: 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 affiliationDepartment 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 emaileric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliationDana-Farber Cancer Institute
contact emaileric_fischer@dfci.harvard.edu
dataset submitter
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