Park JY, Lee D, Lee JJ, Gim J, Gunasekaran TI, Choi KY, Kang S, Do AR, Jo J, Park J, Park K, Li D, Lee S, Kim H, Dhanasingh I, Ghosh S, Keum S, Choi JH, Song GJ, Sael L, Rhee S, Lovestone S, Kim E, Moon SH, Kim BC, Kim S, Saykin AJ, Nho K, Lee SH, Farrer LA, Jun GR, Won S, Lee KH,

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 ...

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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?×?10-9) and hippocampal volume (p?=?5.1?×?10-12). It revealed an increased risk of developing AD in the mediation analyses. This variant was also associated with amyloid-? accumulation (p?=?0.03) and measures of memory (p?=?1.0?×?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?×?10-6) and AddNeuroMed (rs138412600, p?=?5.9?×?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-?B signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.

Date: Dec. 16, 2020

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