Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation

Jun Sung Park, Junehawk Lee, Eun Sun Jung, Myeong-Heui Kim, Il Bin Kim, Hyeonju Son, Sangwoo Kim, Sanghyeon Kim, Young Mok Park, Inhee Mook-Jung, Seok Jong Yu () and Jeong Ho Lee ()
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Jun Sung Park: Korea Advanced Institute of Science and Technology (KAIST)
Junehawk Lee: Korea Institute of Science and Technology Information
Eun Sun Jung: Seoul National University
Myeong-Heui Kim: Korea Advanced Institute of Science and Technology (KAIST)
Il Bin Kim: Korea Advanced Institute of Science and Technology (KAIST)
Hyeonju Son: Yonsei University College of Medicine
Sangwoo Kim: Yonsei University College of Medicine
Sanghyeon Kim: Stanley Medical Research Institute (SMRI)
Young Mok Park: Institute for Basic Science (IBS)
Inhee Mook-Jung: Seoul National University
Seok Jong Yu: Korea Institute of Science and Technology Information
Jeong Ho Lee: Korea Advanced Institute of Science and Technology (KAIST)

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11000-7

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