PXD065224

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/09/PXD065224

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