TFEB/LAMP2 contributes to PM_(0.2)-induced autophagy-lysosome dysfunction and alpha-synuclein dysregulation in astrocytes  

作　　者：Ben Li Ting Liu Yongmei Shen Jiangnan Qin Xiaohan Chang Meiqiong Wu Jianquan Guo Liangpo Liu Cailing Wei Yi Lyu Fengjie Tian Jinzhu Yin Tong Wang Wenping Zhang Yulan Qiu 

机构地区：[1]School of Public Health,Shanxi Medical University,Taiyuan 030000,China [2]Hainan Provincial Center for Disease Control and Prevention,Haikou 570100,China [3]Department of Neurosurgery,Sinopharm Tongmei General Hospital,Datong 037003,China [4]Key Laboratory of Coal Environmental Pathogenicity and Prevention(Shanxi Medical University),Ministry of Education,Taiyuan 030000,China

出　　处：《Journal of Environmental Sciences》2024年第11期117-127,共11页环境科学学报（英文版）

基　　金：supported by the National Science Foundation of China(No.21906100);the Applied Basic Research Project of Shanxi Province(Nos.201901D211333,201901D211327,and 202203021211246).

摘　　要：Atmospheric particulatematter(PM)exacerbates the risk factor for Alzheimer’s and Parkinson’s diseases(PD)by promoting the alpha-synuclein(α-syn)pathology in the brain.However,the molecular mechanisms of astrocytes involvement inα-syn pathology underlying the process remain unclear.This study investigated PM with particle size<200 nm(PM_(0.2))exposure-inducedα-syn pathology in ICR mice and primary astrocytes,then assessed the effects of mammalian target of rapamycin inhibitor(PP242)in vitro studies.We observed theα-syn pathology in the brains of exposed mice.Meanwhile,PM_(0.2)-exposed mice also exhibited the activation of glial cell and the inhibition of autophagy.In vitro study,PM_(0.2)(3,10 and 30μg/mL)induced inflammatory response and the disorders ofα-syn degradation in primary astrocytes,and lysosomal-associated membrane protein 2(LAMP2)-mediated autophagy underliesα-syn pathology.The abnormal function of autophagy-lysosome was specifically manifested as the expression of microtubule-associated protein light chain 3(LC3II),cathepsin B(CTSB)and lysosomal abundance increased first and then decreased,which might both be a compensatory mechanism to toxicα-syn accumulation induced by PM_(0.2).Moreover,with the transcription factor EB(TFEB)subcellular localization and the increase in LC3II,LAMP2,CTSB,and cathepsin D proteins were identified,leading to the restoration of the degradation ofα-syn after the intervention of PP242.Our results identified that PM_(0.2)exposure could promote theα-syn pathological dysregulation in astrocytes,providing mechanistic insights into how PM_(0.2)increases the risk of developing PD and highlighting TFEB/LAMP2 as a promising therapeutic target for antagonizing PM_(0.2)toxicity.

关 键 词：PM_(0.2) ASTROCYTES α-Synuclein Autophagy-lysosome 

分 类 号：X51[环境科学与工程—环境工程]