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Somatic genomic changes in single Alzheimer’s disease neurons
Open accessAbstract
Dementia in Alzheimer's disease progresses alongside neurodegeneration 1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations 5 at rates similar to those of dividing cells 6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation 5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells 6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation 4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.
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“This is especially relevant when DNA damage impacts on stem cells, hampering their role in tissue renewal or leading to their exhaustion, which in turn promotes aging and increases susceptibility to age-related pathologies 6,7 .”
From Hallmarks of aging: An expanding universe (2023) · cites this paper as [7]
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“Previous studies have shown increased neuronal genomic mosaicism (including SNVs, copy number variations, and cDNA insertions in neurodegeneration)124–128.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [125]
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Metadata
- Authors
- Miller, M. B., Huang, A. Y., Kim, J., Zhou, Z., Kirkham, S. L., Maury, E. A., Ziegenfuss, J. S., Reed, H. C., Neil, J. E., Rento, L., Ryu, S. C., Ma, C. C., Luquette, L. J., Ames, H. M., Oakley, D. H., Frosch, M. P., Hyman, B. T., Lodato, M. A., Lee, E. A., & Walsh, C. A.
- Affiliations
- Broad Institute (US)
- Boston Children's Hospital (US)
- University of Massachusetts Chan Medical School (US)
- Allegheny College (US)
- Harvard University (US)
- University of Maryland, Baltimore (US)
- Corresponding author
- Lodato, Michael A.
- Lee, Eunjung Alice
- Walsh, Christopher A.
- ORCID
- Venue
- Nature
- Published
- 2022-04-20
- Volume
- 604
- Issue
- 7907
- Pages
- 714-722
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9357465
- OpenAlex
- W4224234680
- Cited by
- 223
- References
- 84
- Citations by year
- 2026: 41 · 2025: 52 · 2024: 57 · 2023: 53 · 2022: 20
- FWCI
- 28.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1t15lm007098-01)
- National Institute on Aging (K08AG065502, DP2AG072437, K01AG051791, R00AG054748, R01AG070921, P30AG062421)
- National Heart, Lung, and Blood Institute (T32HL007627)
- National Human Genome Research Institute (T32HG002295)
- National Institute of General Medical Sciences (T32GM007753)
- National Institute of Neurological Disorders and Stroke (R01NS032457)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD105351)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- Alzheimer's disease, somatic mutations, neuronal DNA damage, mutational signatures, nucleotide oxidation, transcription-coupled repair, prefrontal cortex, hippocampus, neurodegeneration, aging, single-cell whole-genome sequencing
- MeSH terms
- Whole Genome Sequencing, Aging, Alzheimer Disease, DNA, Exons, Hippocampus, Humans, Neurons, Nucleotides, Prefrontal Cortex, Genomics, Mutation Rate
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