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Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease.

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机构： [1]Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China, [2]Department of Psychiatry,Washington University, St. Louis, MO 63110, USA, [3]NeuroGenomics and Informatics Center,Washington University, St. Louis, MO 63110, USA, [4]Department of Genetics,Washington University, St. Louis, MO 63110, USA, [5]Beijing Key Laboratory of Geriatric Cognitive Disorders, Capital Medical University, Beijing 10053, China, [6]Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing 10053, China [7]Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 10053, China

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To identify novel risk genes and better understand the molecular pathway underlying Alzheimer's disease (ad), whole-exome sequencing (WES) was performed in 215 early-onset ad (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOad. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation, and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of ad patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cAMP levels, protein kinase A (PKA) activation, and cAMP response element-binding protein (CREB) phosphorylation. Additionally, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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基金编号： 7192077

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出版当年[2020]版：

大类 | 2 区生物

小类 | 2 区生化与分子生物学 2 区遗传学

最新[2025]版：

大类 | 2 区生物学

小类 | 3 区生化与分子生物学 3 区遗传学

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出版当年[2019]版：

Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Q1 GENETICS & HEREDITY

最新[2023]版：

Q2 GENETICS & HEREDITY Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

影响因子： 3.1 最新[2023版] 4.2 最新五年平均 5.101 出版当年[2019版] 5.362 出版当年五年平均 4.544 出版前一年[2018版] 6.15 出版后一年[2020版]

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第一作者机构： [1]Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China,

通讯作者：

通讯机构： [1]Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing 100053, China, [5]Beijing Key Laboratory of Geriatric Cognitive Disorders, Capital Medical University, Beijing 10053, China, [6]Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical University, Beijing 10053, China [7]Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 10053, China [*1]Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Beijing 100053, P.R. China

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