{
  "abstract": "Cell-to-cell transmission of -synuclein (-Syn) aggregates is a key event in Parkinson's disease (PD) pathogenesis, yet the neuronal surface factors that govern uptake of pathogenic -Syn fibrils remain undefined. We developed a flow cytometry-based CRISPR activation screen for modifiers of -Syn preformed fibril (PFF) uptake by human iPSC-derived cortical neurons. By interrogating 68 genes encoding cell-surface proteins prioritised by PD genetic associations, we identified podocalyxin-like protein 1 (PODXL) as a strong suppressor of -Syn fibril uptake. High-content imaging and PODXL cDNA overexpression confirmed reduced PFF uptake. Stable PODXL overexpression also reduced PFF-seeded pSynSer129 accumulation and uptake of structurally distinct recombinant and disease-derived -Syn fibrils. Conversely, shRNA-mediated PODXL knockdown increased -Syn PFF uptake, and analysis of PODXL domain-deletion and N-glycosylation mutants suggested that the ectodomain and N-glycosylation contribute to the PODXL-mediated reduction in uptake. Transcriptomic profiling further identified membrane metalloendopeptidase (MME) as a PODXL-responsive candidate mediator. MME activation and treatment with conditioned medium from MME-activated neurons reduced PFF uptake. Thiorphan, an MME inhibitor, partially attenuated the PODXL-associated reduction in uptake. Together, our findings identify PODXL as a neuronal brake on -Syn uptake and implicate its glycan-dependent surface properties together with MME-associated extracellular activity.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for the Science of the Aging Brain"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "S. Neupane"
    },
    {
      "name": "L. Sustic"
    },
    {
      "name": "L. Maraio"
    },
    {
      "name": "V. Bouris"
    },
    {
      "name": "G. Mariutti"
    },
    {
      "name": "R. Ribeiro"
    },
    {
      "name": "J.-A. Yin"
    },
    {
      "name": "R. Melki"
    },
    {
      "name": "G. Legname"
    },
    {
      "name": "E. De Cecco"
    },
    {
      "affs": [
        0
      ],
      "name": "A. Aguzzi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/846dzpyzekzey.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.15.759470",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759470v1.full",
  "id": "846dzpyzekzey",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759470v1",
  "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": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2728|Parkinson's Disease Mechanisms and Treatments"
    ]
  ],
  "openalex": "W7223138394",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759470v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/846dzpyzekzey.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:28:52Z",
      "native_id": "10.64898/2026.10.15.759470",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.15.759470v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "PODXL regulates the neuronal entry of α-synuclein aggregates",
  "title_text": "PODXL regulates the neuronal entry of α-synuclein aggregates",
  "type": "preprint",
  "updated_at": "2026-10-30T12:28:52Z",
  "url": "https://research.draconitic.com/paper/846dzpyzekzey",
  "venue": "bioRxiv",
  "versions": []
}