Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6802881 | Neurobiology of Aging | 2018 | 28 Pages |
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E É4 allele (ApoE É4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE É4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aβ42 to Aβ40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE É4-negative AD in the Hong Kong Chinese population.
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Authors
Binbin Wang, Suying Bao, Zhigang Zhang, Xueya Zhou, Jing Wang, Yanhui Fan, Yan Zhang, Yan Li, Luhua Chen, Yizhen Jia, Jiang Li, Miaoxin Li, Wenhua Zheng, Nan Mu, Liqiu Wang, Zhe Yu, Dana S.M. Wong, Yalun Zhang, You-Qiang Song,