{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Montreal Neurological Institute, McGill University"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 26,
  "authors": [
    {
      "name": "N. C. Karpilovsky"
    },
    {
      "name": "T. Goiran"
    },
    {
      "name": "K. Senkevich"
    },
    {
      "name": "G. Deyab"
    },
    {
      "name": "N. Twells"
    },
    {
      "name": "E. N. Cha"
    },
    {
      "name": "E. J. MacDougall"
    },
    {
      "name": "Z. Wang"
    },
    {
      "name": "J. Sirois"
    },
    {
      "name": "G. Macleod"
    },
    {
      "name": "L. Liu"
    },
    {
      "name": "M. Ghamgosar Shahkhali"
    },
    {
      "name": "K. Ali Boubacar"
    },
    {
      "name": "J. Jones-Tabah"
    },
    {
      "name": "I. Pietrantonio"
    },
    {
      "name": "W. Luo"
    },
    {
      "name": "I. Shlaifer"
    },
    {
      "name": "E. Del Cid-Pellitero"
    },
    {
      "name": "A. Kulepa"
    },
    {
      "name": "E. B. Affar"
    },
    {
      "name": "S. Angers"
    },
    {
      "name": "J. Liu"
    },
    {
      "name": "L. K. Mahal"
    },
    {
      "name": "T. M. Durcan"
    },
    {
      "name": "Z. Gan-Or"
    },
    {
      "affs": [
        0
      ],
      "name": "E. A. Fon"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/099pv30wcgrpk.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.09.26362627",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362627v1.full",
  "id": "099pv30wcgrpk",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362627v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ],
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7212353985",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362627v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/099pv30wcgrpk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:23Z",
      "native_id": "10.64898/2026.09.09.26362627",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.09.26362627v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "The Parkinson 's Disease Associated BAP1/ASXL3 Complex Regulates the Internalization of α-Synuclein Fibrils by Reprogramming the Cell Surface Glycoproteome",
  "title_text": "The Parkinson 's Disease Associated BAP1/ASXL3 Complex Regulates the Internalization of α-Synuclein Fibrils by Reprogramming the Cell Surface Glycoproteome",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:23Z",
  "url": "https://research.draconitic.com/paper/099pv30wcgrpk",
  "venue": "medRxiv",
  "versions": []
}