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Somatic genomic changes in single Alzheimer's disease neurons.
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.
Afiliación
  • Miller MB; Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Huang AY; Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
  • Kim J; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Zhou Z; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Kirkham SL; Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
  • Maury EA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ziegenfuss JS; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Reed HC; Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
  • Neil JE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Rento L; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Ryu SC; Department of Biological Sciences, Sungkyunkwan University, Suwon, South Korea.
  • Ma CC; Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
  • Luquette LJ; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Ames HM; Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
  • Oakley DH; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Frosch MP; Division of Genetics and Genomics, Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA.
  • Hyman BT; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lodato MA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
  • Lee EA; Bioinformatics and Integrative Genomics Program, Harvard-MIT MD-PhD Program, Harvard Medical School, Boston, MA, USA.
  • Walsh CA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Nature ; 604(7907): 714-722, 2022 04.
Article en En | MEDLINE | ID: mdl-35444284
Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, 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 cells6-10. 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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Neuronas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Neuronas Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nature Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos