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

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.