ArticleCell2026
Recurrent patterns of TOP1-mediated neuronal genomic damage shared by major neurodegenerative disorders.
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Article in Cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13citing papers in PubMed
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Who cites it
13 citing papers in PubMed.
- Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.Neural regeneration research · 2026Article
- At high noon, plants apply a condensate sunscreen.Nature reviews. Molecular cell biology · 2026Article
- Article
- Double strand breaks drive toxicity in a Huntington's disease mouse model with or without somatic expansion.Nature communications · 2026Article
- Duplex-Indel: a Snakemake pipeline for somatic Indel calling in Tn5 transposase-based duplex sequencing data.Bioinformatics (Oxford, England) · 2026Article
- Decoding neurodegeneration one cell at a time.The Journal of clinical investigation · 2026Review
- Somatic mutation in human cerebellum illustrates neuron type-specific patterns of age-related mutation.bioRxiv : the preprint server for biology · 2026Article
- Benchmarking of duplex sequencing approaches to reveal somatic mutation landscapes.bioRxiv : the preprint server for biology · 2025Article
- Review
- Diverse somatic genomic alterations in single neurons in chronic traumatic encephalopathy.Science (New York, N.Y.) · 2025Article
- Brain somatic mutations in Alzheimer's disease: linking genetic mosaicism to neurodegeneration.Molecular neurodegeneration · 2025Review
- Double strand breaks drive toxicity in Huntington's disease mice with or without somatic expansion.bioRxiv : the preprint server for biology · 2025Article
- New insights into Rett syndrome pathogenesis: defining the role of MEPC2 in DNA damage.Frontiers in neurologyReview
Corrections and comments
- Update of
Authors and funding
21 authors.
Zinan ZhouDivision 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.
Lovelace J LuquetteDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: lovelace_luquette@hms.harvard.edu.
Guanlan DongDivision 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.
Junho KimDivision 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.
Jayoung KuDivision 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.
Kisong KimDivision 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.
Nandini RameshDepartment 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.
Mingyun BaeDivision 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.
Ann CaplinDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Diane D ShaoDivision 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.
Bezawit SahileProgram in Neuroscience, Harvard Medical School, Boston, MA, USA.
Kow EssumanDivision 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.
Eitan GoodmanDivision of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
Michael B MillerDivision 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.
August Yue HuangDivision 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.
William J NathanLaboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Andre NussenzweigLaboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Peter J ParkDepartment of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. Electronic address: peter_park@hms.harvard.edu.
Clotilde Lagier-TourenneDepartment 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.
Eunjung Alice LeeDivision 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.
Christopher A WalshDivision 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.
Funding
Cell Identity Determination In Human Brain: Somatic Mutation and Cell LineageR01NS032457 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI Alice Eunjung Lee, Christopher A. Walsh · 1995 to 2026
$12.7MTargeting Dysregulated RNA Splicing in Neurodegenerative DiseasesRM1NS133601 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI Clotilde Lagier-Tourenne, Michael Emmerson Ward · 2023 to 2026
$7.4MRole of clonal somatic mutations in microglia and Alzheimer’s diseaseR01AG088082 · NIA · BOSTON CHILDREN'S HOSPITAL · PI Yue Huang · 2024 to 2026
$4.4MRates and mechanisms of age-related somatic mutation in normal and Alzheimer brainR01AG070921 · NIA · BOSTON CHILDREN'S HOSPITAL · PI LEE, ALICE EUNJUNG, WALSH, CHRISTOPHER A. · 2021 to 2025
$4.3MDevelopment and Application of Computational Methods for Single Cell DNA Sequencing DataR01HG012573 · NHGRI · HARVARD MEDICAL SCHOOL · PI PARK, PETER J · 2022 to 2025
$2.7MIlluminating neurodegenerative tauopathy from somatic genomic landscapes of single human brain cellsDP2AG086138 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI Michael B Miller · 2023 to 2026
$2.7MMechanisms of Somatic Mutation in Alzheimer's Disease Using Single Neuron AnalysisR01AG082346 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI Michael B Miller · 2024 to 2026
$2.7MMechanism for endogenous retroelements to mimic ancient exogenous identities in aging and diseased human tissueDP2AG072437 · NIA · BOSTON CHILDREN'S HOSPITAL · PI LEE, EUNJUNG ALICE · 2020 to 2020
$2.7MRole of clonal somatic mutations in microglia activation and Alzheimer’s diseaseR56AG079857 · NIA · BOSTON CHILDREN'S HOSPITAL · PI HUANG, YUE, LEE, EUNJUNG ALICE · 2023 to 2023
$883kDetection and Characterization of Somatic Mutations in Human Tissue Utilizing Duplex-Consensus SequencingUG3NS132144 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI CHOUDHURY, SANGITA, LEE, EUNJUNG ALICE · 2023 to 2024
$877kDevelopment of an Efficient High Throughput Technique for the Identification of High-Impact Non-Coding Somatic Variants Across Multiple Tissue TypesUG3NS132138 · NINDS · BOSTON CHILDREN'S HOSPITAL · PI PARK, PETER J, WALSH, CHRISTOPHER A. · 2023 to 2024
$870kThe role of somatic mutation in neurodegenerative diseaseK01AG051791 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI LEE, EUNJUNG ALICE · 2016 to 2020
$655kNHGRI NIH HHS R01 HG012573NIA NIH HHS DP2 AG072437NIA NIH HHS DP2 AG086138NIA NIH HHS K01 AG051791NIA NIH HHS R01 AG070921NIA NIH HHS R01 AG082346NIA NIH HHS R01 AG088082NIA NIH HHS R56 AG079857NINDS NIH HHS R01 NS032457NINDS NIH HHS RM1 NS133601NINDS NIH HHS UG3 NS132138NINDS NIH HHS UG3 NS132144
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.
Indexed as
Amyotrophic Lateral SclerosisDNA Topoisomerases, Type INeurodegenerative DiseasesNeuronsAlzheimer DiseaseC9orf72 ProteinDNA-Binding ProteinsDNA DamageFrontotemporal DementiaHumansC9orf72 ProteinC9orf72 protein, humanDNA-Binding ProteinsDNA Topoisomerases, Type ITARDBP protein, humanTOP1 protein, humanAlzheimer’s diseaseamyotrophic lateral sclerosisDNA damageDNA strand breaksfrontotemporal dementiagenomic instabilitymutation signatureribonucleotide excision repairsomatic mutationtopoisomerase 1
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.