{
  "abstract": "Currently, pathological inclusions of ubiquitinated TDP-43 are considered central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, this view has yielded sparse attention to covert alternative pathways of aggregation in the disease. Here, we identified a pathological axis independent of TDP-43 led by ARPP21, a SUZ domain-containing RNA-binding protein encoded by a gene recently described in strong association with ALS. ARPP21 showed large fibrillar non-ubiquitinated aggregates in all the non-SOD1 ALS cases studied, consistently segregating from TDP-43 pathology. Biophysically, ARPP21 undergoes spontaneous phase separation, with a higher propensity for condensate formation than TDP-43 but without co-aggregating with it. ARPP21 also exhibited very slow soluble behavior and lower condensate dynamics compared to TDP-43, an effect that was more pronounced for the ARPP21-P529L disease-related variant. In human iPSC-derived motor neurons, expression of ARPP21 variants was sufficient to drive condensate formation and reduce cell viability. Mechanistically, ARPP21 promoted intercellular propagation by inducing tunnelling nanotube formation, enabling efficient cell-to-cell spreading of aggregates. Genetic analyses further identified multiple ARPP21 variants in ALS, supporting its clinical relevance. Together, our findings uncover ARPP21 as a previously unrecognized TDP-43-independent aggregation pathway in ALS, with implications for disease heterogeneity and therapeutic targeting.",
  "abstract_shown": true,
  "affiliations": [
    "Molecular Medicine Group, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, Canada"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "D. Campos-Melo"
    },
    {
      "name": "A. A. Dilliott"
    },
    {
      "name": "S. M. K. Farhan"
    },
    {
      "name": "M. J. Strong"
    },
    {
      "affs": [
        0
      ],
      "name": "C. A. Droppelmann"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/40zc30fqkrnnt.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.08.750091",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.08.750091v1.full",
  "id": "40zc30fqkrnnt",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.08.750091v1",
  "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|Amyotrophic Lateral Sclerosis Research"
    ]
  ],
  "openalex": "W7213033897",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.08.750091v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/40zc30fqkrnnt.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:20Z",
      "native_id": "10.64898/2026.09.08.750091",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.08.750091v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "ARPP21 defines a TDP-43-independent aggregation pathway in amyotrophic lateral sclerosis",
  "title_text": "ARPP21 defines a TDP-43-independent aggregation pathway in amyotrophic lateral sclerosis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:20Z",
  "url": "https://research.draconitic.com/paper/40zc30fqkrnnt",
  "venue": "bioRxiv",
  "versions": []
}