Cited by 223Alzheimer's disease research and treatmentsDNA Repair MechanismsCancer Genomics and Diagnostics

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Somatic genomic changes in single Alzheimer’s disease neurons

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Miller, Michael B., Huang, August Yue, Kim, Junho, Zhou, Zinan, Kirkham, Samantha L., Maury, Eduardo A., Ziegenfuss, Jennifer S., Reed, Hannah C., Neil, Jennifer E., Rento, Lariza, Ryu, Steven C., Ma, Chanthia C., Luquette, Lovelace J., Ames, Heather M., Oakley, Derek H., Frosch, Matthew P., Hyman, Bradley T., Lodato, Michael A., Lee, Eunjung Alice, Walsh, Christopher A.·2022·Nature

DOI 10.1038/s41586-022-04640-1PMC PMC9357465

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Abstract

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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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: Miller, Michael B.
Huang, August Yue
Zhou, Zinan
Kirkham, Samantha L.
Maury, Eduardo A.
Ziegenfuss, Jennifer S.
Rento, Lariza
Ryu, Steven C.
Ma, Chanthia C.
Luquette, Lovelace J.
Ames, Heather M.
Oakley, Derek H.
Frosch, Matthew P.
Hyman, Bradley T.
Lodato, Michael A.
Lee, Eunjung Alice
Walsh, Christopher A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2022-04-20
Volume: 604
Issue: 7907
Pages: 714-722
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-022-04640-1
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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Somatic genomic changes in single Alzheimer’s disease neurons

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