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Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils
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Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils
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Journal Article
Novel regulators of heparan sulfate proteoglycans modulate cellular uptake of α-synuclein fibrils
2025
Overview
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.
Genome-wide CRISPR/Cas9 screening reveals novel modulators of heparan sulfate proteoglycans that regulate cellular uptake of α-synuclein fibrils, including in human dopaminergic neurons.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ alpha-Synuclein - metabolism
/ Animals
/ Biomedical and Life Sciences
/ Cation Transport Proteins - genetics
/ Cation Transport Proteins - metabolism
/ CRISPR
/ Fibrils
/ Genes
/ Genomes
/ Golgi Apparatus - metabolism
/ Heparan sulfate proteoglycans
/ Heparan Sulfate Proteoglycans - metabolism
/ Humans
/ Kinases
/ Mice
/ Ontology
/ Proteins
/ Sulfates
/ Zinc
