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A missense variant in SHARPIN mediates Alzheimer's disease-specific brain damages

Cited 9 time in Web of Science Cited 10 time in Scopus
Authors

Park, Jun Young; Lee, Dongsoo; Lee, Jang Jae; Gim, Jungsoo; Gunasekaran, Tamil Iniyan; Choi, Kyu Yeong; Kang, Sarang; Do, Ah Ra; Jo, Jinyeon; Park, Juhong; Park, Kyungtaek; Li, Donghe; Lee, Sanghun; Kim, Hoowon; Dhanasingh, Immanuel; Ghosh, Suparna; Keum, Seula; Choi, Jee Hye; Song, Gyun Jee; Sael, Lee; Rhee, Sangmyung; Lovestone, Simon; Kim, Eunae; Moon, Seung Hwan; Kim, Byeong C.; Kim, SangYun; Saykin, Andrew J.; Nho, Kwangsik; Lee, Sung Haeng; Farrer, Lindsay A.; Jun, Gyungah R.; Won, Sungho; Lee, Kun Ho

Issue Date
2021-11
Publisher
Nature Publishing Group
Citation
Translational Psychiatry, Vol.11 No.1, p. 590
Abstract
Established genetic risk factors for Alzheimer's disease (AD) account for only a portion of AD heritability. The aim of this study was to identify novel associations between genetic variants and AD-specific brain atrophy. We conducted genome-wide association studies for brain magnetic resonance imaging measures of hippocampal volume and entorhinal cortical thickness in 2643 Koreans meeting the clinical criteria for AD (n = 209), mild cognitive impairment (n = 1449) or normal cognition (n = 985). A missense variant, rs77359862 (R274W), in the SHANK-associated RH Domain Interactor (SHARPIN) gene was associated with entorhinal cortical thickness (p = 5.0 x 10(-9)) and hippocampal volume (p = 5.1 x 10(-12)). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-beta accumulation (p = 0.03) and measures of memory (p = 1.0 x 10(-4)) and executive function (p = 0.04). We also found significant association of other SHARPIN variants with hippocampal volume in the Alzheimer's Disease Neuroimaging Initiative (rs3417062, p = 4.1 x 10(-6)) and AddNeuroMed (rs138412600, p = 5.9 x 10(-5)) cohorts. Further, molecular dynamics simulations and co-immunoprecipitation indicated that the variant significantly reduced the binding of linear ubiquitination assembly complex proteins, SHPARIN and HOIL-1 Interacting Protein (HOIP), altering the downstream NF-kappa B signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
ISSN
2158-3188
URI
https://hdl.handle.net/10371/180068
DOI
https://doi.org/10.1038/s41398-021-01680-5
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Graduate School of Public Health (보건대학원)Dept. of Public Health (보건학과)Journal Papers (저널논문_보건학과)
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