한빛사논문
- 조회1,091
Michael B. Miller1,2,3,4,14, August Yue Huang2,3,4,14, Junho Kim2,3,4,5, Zinan Zhou2,4, Samantha L. Kirkham2,4, Eduardo A. Maury2,3,4,6, Jennifer S. Ziegenfuss7, Hannah C. Reed2,4,8, Jennifer E. Neil2,4,9, Lariza Rento2,4,9, Steven C. Ryu2,4, Chanthia C. Ma2,4, Lovelace J. Luquette10, Heather M. Ames11, Derek H. Oakley12, Matthew P. Frosch12,13, Bradley T. Hyman13, Michael A. Lodato2,4,7,16,*, Eunjung Alice Lee2,3,4,16,* & Christopher A. Walsh2,3,4,9,14,16,*
1Division of Neuropathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. 2Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children’s Hospital, Boston, MA, USA. 3Broad Institute of MIT and Harvard, Cambridge, MA, USA. 4Department of Pediatrics, Harvard Medical School, Boston, MA, USA. 5Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea. 6Bioinformatics and Integrative Genomics Program, Harvard–MIT MD–PhD Program, Harvard Medical School, Boston, MA, USA. 7Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA. 8Allegheny College, Meadville, PA, USA. 9Howard Hughes Medical Institute, Boston, MA, USA. 10Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. 11Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA. 12Department of Pathology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. 13Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA. 14Department of Neurology, Harvard Medical School, Boston, MA, USA. 15These authors contributed equally: Michael B. Miller, August Yue Huang. 16These authors jointly supervised this work: Michael A. Lodato, Eunjung Alice Lee, Christopher A. Walsh.
*Corresponding author.
Abstract
Dementia in Alzheimer’s disease progresses alongside neurodegeneration1,2,3,4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. 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 cells6,7,8,9,10. 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 oxidation4,11, 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.
논문정보
- Research article
- 2022년 04월 (BRIC 등록일 2022-06-09)
- 국내+국외 연구진
- 의약학 > 유전 및 유전체의학
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