PXD055581

PXD055581 is an original dataset announced via ProteomeXchange.

Title	Spatiotemporal resolution of α-synuclein pathology in human dopaminergic neurons implicates defective ER translocation in Parkinson’s disease
Description	Parkinson’s disease is the second most common neurodegenerative disease, currently without any disease modifying therapy. Although α-synuclein is causatively linked to Parkinson’s pathogenesis, the primary mechanism and subcellular localisation of early cytotoxicity as well as its most damaging proteoform remain unknown. To address this issue, we spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We show that microscale α-synuclein aggregates are biochemically inert whereas nanoscale aggregates, not visible by conventional confocal microscopy, are associated with impaired Sec61A translocon function at the endoplasmic reticulum (ER). α-Synuclein blocks the cotranslational translocation of ER-processed proteins including the vacuolar-type ATPase V0a1 subunit, glucocerebrosidase, and VPS13C, causing defective organelle function, as exemplified by measurements of lysosomal acidification, secondary UFMylation and proteasomal recruitment without activation of the unfolded protein response. Reduction of nano-aggregate abundance using either CRISPRi to decrease α-synuclein expression or rolipram to activate proteasomal degradation mitigate the ER translocation defect. Our study offers a unifying mechanistic link between early α-synuclein pathology and dysregulation of diverse organelle-associated proteins that are both translocon substrates and genetic modifiers. Importantly, our data suggest that proteasomal activation with repurposed drugs should be considered for therapeutic intervention in patients with early-stage pathology.
HostingRepository	PRIDE
AnnounceDate	2026-08-20
AnnouncementXML	Submission_2026-08-19_22:38:28.133.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Svenja Hester
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-05 05:18:25	ID requested
⏵ 1	2026-08-19 22:38:28	announced

10.1038/S41467-026-76173-4;

submitter keyword: ribotoxicity, alpha-synuclein, Parkinson’s disease,Endoplasmic reticulum

Dr. George K. Tofaris
contact affiliation	Nuffield Department of Clinical Neuroscience
contact email	george.tofaris@ndcn.ox.ac.uk
lab head
Svenja Hester
contact affiliation	Nuffield Department of Medicine
contact email	svenja.hester@ndm.ox.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055581
     1. Label: PRIDE project
     2. Name: Spatiotemporal resolution of α-synuclein pathology in human dopaminergic neurons implicates defective ER translocation in Parkinson’s disease