Nature communications, 2019-07, Vol.10 (1), p.3090-12, Article 3090
2019
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- Autor(en) / Beteiligte
- Titel
- Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation
- Ist Teil von
- Nature communications, 2019-07, Vol.10 (1), p.3090-12, Article 3090
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- The role of brain somatic mutations in Alzheimer’s disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD. The role of brain somatic mutations in neurodegenerative diseases such as Alzheimer’s disease (AD) is not well understood. Here the authors carry out high-depth exome sequencing ~500× on brain tissue from patients with AD and controls, and identify mutations in a number of genes that are known to contribute to phosphorylation and aggregation of tau, including PIN1.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-11000-7Titel-ID: cdi_doaj_primary_oai_doaj_org_article_b694e92a879449b6991c1d1dd1d2b943
- Format
- –
- Schlagworte
- 1-Phosphatidylinositol 3-kinase, 13/51, 13/89, 14/63, 45/22, 45/23, 631/208/737, 631/378/1689/1283, 82/80, Age Factors, Aged, Aged, 80 and over, Aging, Aging - genetics, AKT protein, Alzheimer Disease - genetics, Alzheimer Disease - pathology, Alzheimer's disease, Animals, Blood, Brain, Cell Line, Tumor, Female, Gene Knockdown Techniques, Haploinsufficiency, Hippocampus, Hippocampus - cytology, Hippocampus - pathology, Humanities and Social Sciences, Humans, Loss of Function Mutation, Male, MAP kinase, Mice, Middle Aged, Mimicry, multidisciplinary, Mutation, Mutation Rate, Neurons, NIMA-Interacting Peptidylprolyl Isomerase - genetics, NIMA-Interacting Peptidylprolyl Isomerase - metabolism, Nucleotides, Pathogenesis, Phosphorylation, Phosphorylation - genetics, Pin1 protein, Polymorphism, Single Nucleotide, Protein Aggregation, Pathological - genetics, Protein Aggregation, Pathological - pathology, Recombinant Proteins - genetics, Recombinant Proteins - metabolism, Science, Science (multidisciplinary), Tau protein, tau Proteins - metabolism, Whole Exome Sequencing