PXD038364-1

PXD038364 is an original dataset announced via ProteomeXchange.

Title	Monitoring α-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation
Description	While defective α-synuclein homeostasis is central to the pathogenesis of Parkinson’s, fundamental questions about its intracellular trafficking remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of α-synuclein. We identified lysine residues 45, 58 and 60 as critical ubiquitination sites for the degradation of α-synuclein. This is mediated by NBR1 binding to ubiquitinated α-synuclein and entry into endosomes in a process that involves ESCRT I-III complexes for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 are dispensable for this pathway. Antibodies against diglycine-modified α-synuclein peptides confirmed that endogenous α-synuclein is similarly ubiquitinated in brain and targeted to the lysosome in rat primary and human iPSC-derived neurons. Ubiquitinated α-synuclein was detected in Lewy bodies and cellular models of aggregation suggesting that it may be entrapped with endo/lysosomes in inclusion bodies. Collectively, our data elucidate the intracellular trafficking of de novo ubiquitinated α-synuclein and provide the tools for investigating the rapidly turned-over fraction of this disease-causing protein.
HostingRepository	PRIDE
AnnounceDate	2023-05-17
AnnouncementXML	Submission_2023-05-17_06:49:55.850.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	RomanFischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitinylated lysine
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-25 07:02:48	ID requested
⏵ 1	2023-05-17 06:49:56	announced

Dataset with its publication pending

submitter keyword: Ubiquitination, degradation, Parkinson's, homeostasis,α-synuclein

RomanFicher
contact affiliation	Discovery Proteomics Facility Target Discovery Institute University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
lab head
RomanFischer
contact affiliation	University of Oxford
contact email	roman.fischer@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038364
     1. Label: PRIDE project
     2. Name: Monitoring α-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation