Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

查看全文 作　　者：Xiaoyan [1,2]Xu;Yaqin [1]Sun;Xufeng [1]Cen;Bing [4]Shan;Qingwei [1]Zhao;Tingxue [1]Xie;Zhe [5]Wang;Tingjun [5]Hou;Yu [6]Xue;Mengmeng [4]Zhang;Di [6]Peng;Qiming [1]Sun;Cong [1]Yi;Ayaz [3]Najafov;Hongguang [1,2]Xia

机构地区：[1]Department of Biochemistry&Research Center of Clinical Pharmacy of The First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310058,China;[2]Liangzhu Laboratory,Zhejiang University Medical Center,Hangzhou 311121,China;[3]Department of Cell Biology,Harvard Medical School,Boston,MA 02115,USA;[4]Interdisciplinary Research Center on Biology and Chemistry,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 201203,China;[5]College of Pharmaceutical Sciences,Hangzhou Institute of innovative Medicine,Zhejiang University,Hangzhou 310058,China;[6]Key Laboratory of Molecular Biophysics of Ministry of Education,Hubei Bioinformatics and Molecular Imaging Key Laboratory,College of Life Science and Technology,Huazhong University of Science and Technology,Wuhan 430074,China

出　　处：《Protein & Cell》索引2021年第12卷第10期,共19页

基　　金：Financial support was received from the National Key R&D Program of China(2017YFA0104200);the National Natural Science Foundation of China(No.91854108,81773182 and 31601121). 摘　　要：Chaperone-mediated autophagy(CMA)is a lysosome-dependent selective degradation pathway implicated in the pathogenesis of cancer and neurodegenerative diseases.However,the mechanisms that regulate CMA are not fully understood.Here,using unbiased drug screening approaches,we discover Metformin,a drug that is commonly the first medication prescribed for type 2 diabetes,can induce CMA.We delineate the mechanism of CMA induction by Metformin to be via activation of TAK1-IKKα/β signaling that leads to phosphorylation of Ser85 of the key mediator of CMA,Hsc70,and its activation.Notably,we find that amyloid-beta precursor protein(APP)is a CMA substrate and that it binds to Hsc70 in an IKKα/β-dependent manner.The inhibition of CMA-mediated degradation of APP enhances its cytotoxicity.Importantly,we find that in the APP/PS1 mouse model of Alzheimer's disease(AD),activation of CMA by Hsc70 overexpression or Metformin potently reduces the accumulated brain Aβplaque levels and reverses the molecular and behavioral AD phenotypes.Our study elucidates a novel mechanism of CMA regulation via Metformin-TAK1-IKKα/β-Hsc70 signaling and suggests Metformin as a new activator of CMA for diseases,such as AD,where such therapeutic intervention could be beneficial. 关键词：chaperone-mediated autophagy METFORMIN TAK1 IKKα/β Hsc70 APP Alzheimer’s disease

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Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model

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