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A missense variant in SHARPIN mediates Alzheimer's disease-specific brain damages.
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.
Afiliación
  • Park JY; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Lee D; Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Korea.
  • Lee JJ; Neurozen Inc., Seoul, Korea.
  • Gim J; Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Korea.
  • Gunasekaran TI; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Choi KY; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Kang S; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Do AR; Department of Biomedical Science, Chosun University, Gwangju, Korea.
  • Jo J; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Park J; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Park K; Department of Life Science, Chosun University, Gwangju, Korea.
  • Li D; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
  • Lee S; Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Korea.
  • Kim H; Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, Korea.
  • Dhanasingh I; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
  • Ghosh S; Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Korea.
  • Keum S; Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
  • Choi JH; Department of medical consilience, Graduate school, Dankook university, Cheonan, Korea.
  • Song GJ; Gwangju Alzheimer's & Related Dementia cohort research center, Chosun University, Gwangju, Korea.
  • Sael L; Department of Neurology, Chosun University Hospital, Gwangju, Korea.
  • Rhee S; Department of Biomedical Science, Chosun University, Gwangju, Korea.
  • Lovestone S; Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Korea.
  • Kim E; Department of Biomedical Science, Chosun University, Gwangju, Korea.
  • Moon SH; Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Korea.
  • Kim BC; Department of Life Science, Chung-Ang University, Seoul, Korea.
  • Kim S; Department of Life Science, Chung-Ang University, Seoul, Korea.
  • Saykin AJ; Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, Korea.
  • Nho K; Department of Software and Computer Engineering, Ajou University, Suwon-si, Korea.
  • Lee SH; Department of Life Science, Chung-Ang University, Seoul, Korea.
  • Farrer LA; Department of Psychiatry, University of Oxford, Oxford, UK.
  • Jun GR; College of Pharmacy, Chosun University, Gwangju, Korea.
  • Won S; Department of Nuclear Medicine, Samsung Medical Center, Seoul, Korea.
  • Lee KH; Department of Neurology, Chonnam National University Medical School, Gwangju, Korea.
Transl Psychiatry ; 11(1): 590, 2021 11 16.
Article en En | MEDLINE | ID: mdl-34785643
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 × 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-ß 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-κB signaling pathway. These findings suggest that SHARPIN plays an important role in the pathogenesis of AD.
Asunto(s)

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Disfunción Cognitiva Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Transl Psychiatry Año: 2021 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Disfunción Cognitiva Tipo de estudio: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Transl Psychiatry Año: 2021 Tipo del documento: Article