{
  "abstract": "Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD) represent two major categories of neurodegenerative disorders-TAR DNA-binding protein 43 (TDP-43) and tau proteinopathies-for which the mechanisms driving neuronal death remain unclear. Single-cell whole-genome sequencing of 469 neurons from C9ORF72 ALS, C9ORF72 FTD, AD, and control brains revealed increased somatic single-nucleotide variants (sSNVs) and insertions/deletions (sIndels) in all three diseases. Mutational signature analysis identified a disease-associated sSNV signature consistent with oxidative damage and an sIndel process affecting 22% of ALS, 76% of FTD, and 61% of AD neurons-but only 2% of control neurons-resembling signature ID4, previously linked to topoisomerase 1 (TOP1)-mediated mutagenesis. Rapid approach to DNA adduct recovery (RADAR) assays confirmed increased TOP1-DNA covalent complexes, and duplex sequencing confirmed the increased sIndels and identified single-strand events as likely precursor lesions. TOP1-associated sIndel mutagenesis and genome instability thus represent a mechanism shared by both TDP-43 and tau neurodegeneration.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Electronic address: zinan.zhou@childrens.harvard.edu",
    "Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: lovelace_luquette@hms.harvard.edu",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Bioinformatics and Integrative Genomics Program, Harvard Medical School, Boston, MA, USA",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA",
    "Department of Neurology, Sean M. Healey & AMG Center for ALS, Mass General Brigham, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA",
    "Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA",
    "Program in Neuroscience, Harvard Medical School, Boston, MA, USA",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Neurosurgery, Mass General Brigham, Harvard Medical School, Boston, MA, USA",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Division of Neuropathology, Department of Pathology, Mass General Brigham, Harvard Medical School, Boston, MA, USA",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA",
    "Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA",
    "Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: peter_park@hms.harvard.edu",
    "Department of Neurology, Sean M. Healey & AMG Center for ALS, Mass General Brigham, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Electronic address: clagier-tourenne@mgh.harvard.edu",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA. Electronic address: ealee@childrens.harvard.edu",
    "Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Boston, MA, USA. Electronic address: christopher.walsh@childrens.harvard.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Zinan Zhou",
      "orcid": "0000-0003-2014-3650"
    },
    {
      "affs": [
        1
      ],
      "name": "Lovelace J. Luquette",
      "orcid": "0000-0001-6968-9043"
    },
    {
      "affs": [
        2
      ],
      "name": "Guanlan Dong",
      "orcid": "0000-0002-4747-6036"
    },
    {
      "affs": [
        3
      ],
      "name": "Junho Kim",
      "orcid": "0000-0003-3513-401X"
    },
    {
      "affs": [
        4
      ],
      "name": "Jayoung Ku",
      "orcid": "0000-0002-4112-4582"
    },
    {
      "affs": [
        4
      ],
      "name": "K M Kim"
    },
    {
      "affs": [
        5
      ],
      "name": "Nandini Ramesh",
      "orcid": "0000-0003-0860-2922"
    },
    {
      "affs": [
        4
      ],
      "name": "Mingyun Bae",
      "orcid": "0009-0000-8144-476X"
    },
    {
      "affs": [
        6
      ],
      "name": "Ann H. Caplin",
      "orcid": "0000-0002-3384-9049"
    },
    {
      "affs": [
        7
      ],
      "name": "Diane D. Shao",
      "orcid": "0000-0003-2087-4082"
    },
    {
      "affs": [
        8
      ],
      "name": "Bezawit Sahile",
      "orcid": "0000-0003-0085-6573"
    },
    {
      "affs": [
        9
      ],
      "name": "Kow Essuman",
      "orcid": "0000-0002-6781-7248"
    },
    {
      "affs": [
        10
      ],
      "name": "Eitan Goodman",
      "orcid": "0009-0004-8461-6407"
    },
    {
      "affs": [
        11
      ],
      "name": "Michael B. Miller",
      "orcid": "0000-0002-6205-3314"
    },
    {
      "affs": [
        12
      ],
      "name": "August Yue Huang",
      "orcid": "0000-0002-0416-2854"
    },
    {
      "affs": [
        13
      ],
      "name": "William J. Nathan",
      "orcid": "0000-0003-2752-7630"
    },
    {
      "affs": [
        13
      ],
      "name": "André Nussenzweig",
      "orcid": "0000-0002-8952-7268"
    },
    {
      "affs": [
        14
      ],
      "name": "Peter J. Park",
      "orcid": "0000-0001-9378-960X"
    },
    {
      "affs": [
        15
      ],
      "name": "Clotilde Lagier‐Tourenne",
      "orcid": "0000-0002-3058-8322"
    },
    {
      "affs": [
        16
      ],
      "name": "Eunjung Alice Lee",
      "orcid": "0000-0002-6574-9261"
    },
    {
      "affs": [
        17
      ],
      "name": "Christopher A. Walsh",
      "orcid": "0000-0002-0156-2238"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/56cezgp6a1m69.bib",
  "cited_by": 16,
  "doi": "10.1016/j.cell.2026.06.013",
  "fulltext_url": null,
  "id": "56cezgp6a1m69",
  "issns": [
    "0092-8674",
    "1097-4172"
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  "landing_url": "https://doi.org/10.1016/j.cell.2026.06.013",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
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      "openalex",
      "2728|Amyotrophic Lateral Sclerosis Research"
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  "pdf_url": "https://www.cell.com/cell/pdf/S0092-8674(26)00700-2.pdf",
  "pmcid": "PMC11908196",
  "pmid": "40093130",
  "published": "2026-07-01",
  "publisher": "Cell Press",
  "ris": "https://research.draconitic.com/paper/56cezgp6a1m69.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:56Z",
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      "url": "https://doi.org/10.1016/j.cell.2026.06.013"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2728|Amyotrophic Lateral Sclerosis Research",
      "subfield": "neurology"
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  ],
  "title": "Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders",
  "title_text": "Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:38Z",
  "url": "https://research.draconitic.com/paper/56cezgp6a1m69",
  "venue": "Cell",
  "versions": []
}