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Peer-reviewedCC BYCell

Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders

  • Zinan Zhou1
  • Lovelace J. Luquette2
  • Guanlan Dong3
  • Junho Kim4
  • Jayoung Ku5
  • K M Kim5
  • Nandini Ramesh6
  • Mingyun Bae5
  • Ann H. Caplin7
  • Diane D. Shao8
  • Bezawit Sahile9
  • Kow Essuman10
9 more authors
  • Eitan Goodman11
  • Michael B. Miller12
  • August Yue Huang13
  • William J. Nathan14
  • André Nussenzweig14
  • Peter J. Park15
  • Clotilde Lagier‐Tourenne16
  • Eunjung Alice Lee17
  • Christopher A. Walsh18
18 affiliations
  1. 1Division 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: [email protected]
  2. 2Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected]
  3. 3Division 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
  4. 4Division 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
  5. 5Division 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
  6. 6Department 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
  7. 7Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
  8. 8Division 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
  9. 9Program in Neuroscience, Harvard Medical School, Boston, MA, USA
  10. 10Division 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
  11. 11Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA
  12. 12Division 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
  13. 13Division 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
  14. 14Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  15. 15Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: [email protected]
  16. 16Department 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: [email protected]
  17. 17Division 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: [email protected]
  18. 18Division 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: [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{zhou2026recurrent,
  title = {{Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders}},
  author = {Zinan Zhou and Lovelace J. Luquette and Guanlan Dong and Junho Kim and Jayoung Ku and K M Kim and Nandini Ramesh and Mingyun Bae and Ann H. Caplin and Diane D. Shao and Bezawit Sahile and Kow Essuman and Eitan Goodman and Michael B. Miller and August Yue Huang and William J. Nathan and André Nussenzweig and Peter J. Park and Clotilde Lagier‐Tourenne and Eunjung Alice Lee and Christopher A. Walsh},
  journal = {Cell},
  year = {2026},
  month = jul,
  doi = {10.1016/j.cell.2026.06.013},
  url = {https://doi.org/10.1016/j.cell.2026.06.013},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders
AU  - Zinan Zhou
AU  - Lovelace J. Luquette
AU  - Guanlan Dong
AU  - Junho Kim
AU  - Jayoung Ku
AU  - K M Kim
AU  - Nandini Ramesh
AU  - Mingyun Bae
AU  - Ann H. Caplin
AU  - Diane D. Shao
AU  - Bezawit Sahile
AU  - Kow Essuman
AU  - Eitan Goodman
AU  - Michael B. Miller
AU  - August Yue Huang
AU  - William J. Nathan
AU  - André Nussenzweig
AU  - Peter J. Park
AU  - Clotilde Lagier‐Tourenne
AU  - Eunjung Alice Lee
AU  - Christopher A. Walsh
PY  - 2026
DA  - 2026/07/01
JO  - Cell
DO  - 10.1016/j.cell.2026.06.013
UR  - https://doi.org/10.1016/j.cell.2026.06.013
AB  - 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.
SN  - 0092-8674
SN  - 1097-4172
ER  -