Suppression of astrocytic autophagy by αB-crystallin contributes to α-synuclein inclusion formation  

作　　者：Shen-zhao Lu Yong-shun Guo Pei-zhou Liang Shu-zhen Zhang Shu Yin Yan-qing Yin Xiao-min Wang Fei Ding Xiao-song Gu Jia-wei Zhou 

机构地区：[1]Institute of Neuroscience,State Key Laboratory of Neuroscience,CAS Center for Excellence in Brain Science and Intelligence Technology,Shanghai Institutes for Biological Sciences,Chinese Academy of Sciences,Shanghai 200031,China [2]School of Future Techology,University of Chinese Academy of Sciences,Beijing 100049,China [3]Center for Brain Disorders Research,Capital Medical University and Center of Parkinson’s Disease,Beijing Institute for Brain Disorders,Beijing 100053,China [4]Co-innovation Center of Neuroregeneration,School of Medicine,Nantong University,Nantong 226001,Jiangsu,China

出　　处：《Translational Neurodegeneration》2019年第1期24-37,共14页转化神经变性病（英文）

基　　金：This work was supported by grants from the Natural Science Foundation of China(31430036,91742116,U1801681);National Key Basic Research Program of China(2015CB553500);Key Research Program of Frontier Sciences(QYZDJ-SSW-SMC002);Strategic Priority Research Program of Chinese Academy of Science(XDB32020100);Shanghai Municipal Science and Technology Major Project(2018SHZDZX05);the Shanghai Municipal Science and Technology Commission(17ZR1435300 to SZZ).

摘　　要：Background:Parkinson’s disease(PD)is characterized by a chronic loss of dopaminergic neurons and the presence of proteinaceous inclusions(Lewy bodies)within some remaining neurons in the substantia nigra.Recently,astroglial inclusion body has also been found in some neurodegenerative diseases including PD.However,the underlying molecular mechanisms of how astroglial protein aggregation forms remain largely unknown.Here,we investigated the contribution ofαB-crystallin(CRYAB),a small heat shock protein,inα-synuclein inclusion formation in astrocytes.Methods:Small interfering RNA(siRNA)-mediated CRYAB(siCRYAB)knockdown or CRYAB overexpression was performed to investigate the impact of CRYAB on the autophagy in human glioblastoma cell line U251 cells.Coimmunoprecipitation(co-IP)and immunoblotting were used to dissect the interaction among multiple proteins.The clearance ofα-synuclein in vitro was evaluated by immunocytochemistry.CRYAB transgenic mice and transgenic mice overexpressing A30P mutant form of humanα-synuclein were used to examine the influence of CRYAB toα-synuclein accumulation in vivo.Results:We found that knockdown of CRYAB in U251 cells or primary cultured astrocytes resulted in a marked augmentation of autophagy activity.In contrast,exogenous CRYAB disrupted the assembly of the BAG3-HSPB8-HSC70 complex via binding with BAG3,thereby suppressing the autophagy activity.Furthermore,CRYAB-regulated autophagy has relevance to PD pathogenesis.Knockdown of CRYAB remarkably promoted cytoplasmic clearance ofα-synuclein preformed fibrils(PFFs).Conversely,selective overexpression of CRYAB in astrocytes markedly suppressed autophagy leading to the accumulation of α-synuclein aggregates in the brain of transgenic mice expressing humanα-synuclein A30P mutant.Conclusions:This study reveals a novel function for CRYAB as a natural inhibitor of astrocytic autophagy and shows that knockdown of CYRAB may provide a therapeutic target against proteinopathies such as synucleinopathies.

关 键 词：αB-crystallin ASTROCYTES Parkinson’s disease AUTOPHAGY 

分 类 号：R73[医药卫生—肿瘤]