The Parkinson 's Disease Associated BAP1/ASXL3 Complex Regulates the Internalization of α-Synuclein Fibrils by Reprogramming the Cell Surface Glycoproteome
- 1Montreal Neurological Institute, McGill University
Abstract
A central hallmark of Parkinsons disease (PD) is the spread of -Synuclein (Syn) aggregates, which is thought to contribute to its progressive nature. To better understand the mechanism of cellular internalization of Syn 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 Syn 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 Syn fibril internalization by remodelling the cell surface glycoproteome.
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BibTeX
@misc{karpilovsky2026parkinson,
title = {{The Parkinson 's Disease Associated BAP1/ASXL3 Complex Regulates the Internalization of α-Synuclein Fibrils by Reprogramming the Cell Surface Glycoproteome}},
author = {N. C. Karpilovsky and T. Goiran and K. Senkevich and G. Deyab and N. Twells and E. N. Cha and E. J. MacDougall and Z. Wang and J. Sirois and G. Macleod and L. Liu and M. Ghamgosar Shahkhali and K. Ali Boubacar and J. Jones-Tabah and I. Pietrantonio and W. Luo and I. Shlaifer and E. Del Cid-Pellitero and A. Kulepa and E. B. Affar and S. Angers and J. Liu and L. K. Mahal and T. M. Durcan and Z. Gan-Or and E. A. Fon},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.09.26362627},
url = {https://www.medrxiv.org/content/10.64898/2026.09.09.26362627v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - The Parkinson 's Disease Associated BAP1/ASXL3 Complex Regulates the Internalization of α-Synuclein Fibrils by Reprogramming the Cell Surface Glycoproteome
AU - N. C. Karpilovsky
AU - T. Goiran
AU - K. Senkevich
AU - G. Deyab
AU - N. Twells
AU - E. N. Cha
AU - E. J. MacDougall
AU - Z. Wang
AU - J. Sirois
AU - G. Macleod
AU - L. Liu
AU - M. Ghamgosar Shahkhali
AU - K. Ali Boubacar
AU - J. Jones-Tabah
AU - I. Pietrantonio
AU - W. Luo
AU - I. Shlaifer
AU - E. Del Cid-Pellitero
AU - A. Kulepa
AU - E. B. Affar
AU - S. Angers
AU - J. Liu
AU - L. K. Mahal
AU - T. M. Durcan
AU - Z. Gan-Or
AU - E. A. Fon
PY - 2026
DA - 2026/09/09
PB - medRxiv
DO - 10.64898/2026.09.09.26362627
UR - https://www.medrxiv.org/content/10.64898/2026.09.09.26362627v1
AB - A central hallmark of Parkinsons disease (PD) is the spread of -Synuclein (Syn) aggregates, which is thought to contribute to its progressive nature. To better understand the mechanism of cellular internalization of Syn 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 Syn 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 Syn fibril internalization by remodelling the cell surface glycoproteome.
ER -