PXD065224-1

PXD065224 is an original dataset announced via ProteomeXchange.

Title	Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils
Description	Synucleinopathies are characterized by the accumulation and propagation of α-synuclein (α-syn) aggregates throughout the brain, leading to neuronal dysfunction and death. In this study, we used an unbiased FACS-based genome-wide CRISPR/Cas9 knockout screening to identify genes that regulate the entry and accumulation of α-syn preformed fibrils (PFFs) in cells. We identified key genes and pathways specifically implicated in α-syn PFFs intracellular accumulation, including heparan sulfate proteoglycans (HSPG) biosynthesis and Golgi trafficking. All confirmed hits affected heparan sulfate (HS), a post-translational modification known to act as a receptor for proteinaceous aggregates including α-syn and tau. Intriguingly, deletion of SLC39A9 and C3orf58 genes, encoding respectively a Golgi-localized exporter of Zn 2+, and the Golgi-localized putative kinase DIPK2A, specifically impaired the uptake of α-syn PFFs, by preventing the binding of PFFs to the cell surface. Mass spectrometry- based analysis of HS chains in SLC39A9-/- and C3orf58-/- cells indicated major defects in HS homeostasis. Additionally, Golgi accumulation of NDST1, a prime HSPG biosynthetic enzyme, was detected in C3orf58-/- cells. Interestingly, C3orf58-/- human iPSC-derived microglia and dopaminergic neurons exhibited a strong reduction in their ability to internalize α-syn PFFs. Altogether, our data identifies new modulators of HSPGs that regulate α-syn PFFs cell surface binding and uptake.
HostingRepository	PRIDE
AnnounceDate	2025-09-25
AnnouncementXML	Submission_2025-09-25_12:21:16.823.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Rony Chidiac
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-19 10:09:48	ID requested
⏵ 1	2025-09-25 12:21:17	announced

10.1038/S42003-025-08786-2;

ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

submitter keyword: protein aggregates, genome-wide screen, CRISPR/Cas9, preformed fibrils, heparan sulfate proteoglycans, Parkinson’s disease,alpha synuclein

Benoît Vanderperre
contact affiliation	Université du Québec à Montréal (UQAM) Département des Sciences Biologiques, SB-3435 Case postale 8888, succursale Centre-Ville Montréal (Québec) H3C 3P8
contact email	vanderperre.benoit@uqam.ca
lab head
Rony Chidiac
contact affiliation	University of Toronto
contact email	rony.chidiac@utoronto.ca
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065224
     1. Label: PRIDE project
     2. Name: Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils