{
  "abstract": "MAPT (Tau) dysregulation is implicated in several neurodegenerative diseases, but its contribution to amyotrophic lateral sclerosis (ALS) is poorly understood. Here we show that mRNA isoforms encoding 4-repeat (4R) Tau are upregulated and cytoplasmically enriched in iPSC-derived motor neurons (MNs) from VCP-mutant and sporadic ALS, without a corresponding change in Tau protein. Using splice-switching antisense oligonucleotides and isoform-specific siRNAs, we find that enhanced 4R expression reduces MN viability, whereas its selective knockdown improves survival, with kinetics more consistent with an RNA-intrinsic effect than altered protein synthesis. Exon 10-containing MAPT RNA shows increased predicted secondary structure, self-association and altered Tau biocondensation in vitro. In post-mortem ALS cervical spinal cord, increased relative exon 10 usage is associated with a higher-risk clinical phenotype and shorter disease duration These findings identify an isoform-specific contribution of MAPT to MN vulnerability in ALS and nominate 4R MAPT RNA as a therapeutic target.",
  "abstract_shown": true,
  "affiliations": [
    "Neurobiology Programme, Life Sciences Institute, Centre for Life Sciences, National University of Singapore"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "H. Crerar"
    },
    {
      "name": "M. Stasi"
    },
    {
      "name": "K. Pal"
    },
    {
      "name": "S. Nuccio"
    },
    {
      "name": "M. Petric-Howe"
    },
    {
      "name": "G. Manferrari"
    },
    {
      "name": "Y. Wang"
    },
    {
      "name": "B. Clarke"
    },
    {
      "name": "M.-D. G. Ruepp"
    },
    {
      "name": "M. Di Antonio"
    },
    {
      "affs": [
        0
      ],
      "name": "R. Patani"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2kncr8pej5tgp.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.22.753400",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753400v1.full",
  "id": "2kncr8pej5tgp",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753400v1",
  "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": "W7214779686",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753400v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2kncr8pej5tgp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:25:06Z",
      "native_id": "10.64898/2026.09.22.753400",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.22.753400v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS",
  "title_text": "Toxicity of MAPT 4R RNA Contributes to Motor Neuron Degeneration in ALS",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:06Z",
  "url": "https://research.draconitic.com/paper/2kncr8pej5tgp",
  "venue": "bioRxiv",
  "versions": []
}