The Parkinson’s Disease Associated BAP1/ASXL3 Complex Regulates the Internalization of α-Synuclein Fibrils by Reprogramming the Cell Surface Glycoproteome
Year: 2026
Type: preprint
Abstract: A central hallmark of Parkinson’s disease (PD) is the spread of α-Synuclein (αSyn) aggregates, which is thought to contribute to its progressive nature. To better understand the mechanism of cellular internalization of αSyn fibrils, we conducted a genome wide CRISPR activation (CRISPRa) screen to identify genetic modifiers of fibril uptake. We report here BRCA-associated protein 1 ( BAP1 ) as a regulator of fibril uptake into cells and validate its association with the genetic risk of PD. BAP1 regulates fibril entry into cells by acting as a master transcriptional regulator of the cell surface glycoproteome. BAP1 downregulates Heparan Sulfate Proteoglycan (HSPG) and upregulates O-linked glycoprotein expression, the net effect of which is to reduce fibril internalization. The effect of enhancing BAP1 expression is cell-type specific, as it reduces αSyn uptake in iPSC-derived dopaminergic neurons, but not in microglia. Using human midbrain organoids with integrated microglia, we find this effect is mediated through ASXL3, another PD risk gene and a component of the BAP1 Polycomb Repressive-Deubiquitinase Complex (PR-DUB). These findings are consistent with higher BAP1 / ASXL3 co-expression in regions of the brain less vulnerable to PD pathology. Together, the work uncovers a novel role for BAP1/ASXL3 in regulating αSyn fibril internalization by remodelling the cell surface glycoproteome.
Source: medRxiv
Authors: Nathan C. Karpilovsky, Thomas Goiran, Konstantin Senkevich, Ghislaine Deyab, Nicholas Twells, Emily NaYoung Cha, Emma Macdougall, Zhangjie Wang, Julien Sirois, Graham Macleod, Lang Liu, Morvarid Ghamgosar Shahkhali, Kalidou Ali Boubacar, Jace Jones-Tabah, Isabella Pietrantonio, Wen Luo, Irina Shlaifer, Esther Del Cid-Pellitero, Ayodeji Kulepa, El Bachir Affar, Stephane Angers, Jian Liu, Lara K. Mahal, Thomas M. Durcan, Ziv Gan-Or, Edward A. Fon
Institutions: Montreal Neurological Institute and Hospital, McGill University, University of Alberta, University of North Carolina at Chapel Hill, University of Toronto, Donnelly Centre for Cellular and Biomolecular Research, Hôpital Maisonneuve-Rosemont, Centre intégré universitaire de santé et de services sociaux de l'Est-de-l'Île-de-Montréal, Université de Montréal
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Award: G2668716943
OpenAlex ID: W7212353985