Ataxin-3介导的蛋白质稳态失衡在神经退行性疾病中的作用研究进展OA

Neurodegenerative diseases(NDDs)are a group of chronic diseases characterized by progressive neuronal loss and functional decline,including Alzheimer's disease(AD),Parkinson's disease(PD),amyotrophic lateral sclerosis(ALS),and spiny cerebellar ataxia type 3(SCA3).Ataxin-3 is an important deubiquitinating enzyme,which participates in the regulation of protein homeostasis by editing the ubiquitin chain configuration of the substrate.In the physiological state,Ataxin-3 is composed of Josephin domain,ubiquitin binding motif and polyglutamine(polyQ)sequence.Ataxin-3 regulates the ubiquitin-proteasome system,autophagy-lysosomal pathway and endoplasmic reticulum associated degradation by deubiquitination function to maintain cell homeostasis.However,when the CAG repeat of ATXN3 gene is abnormally expanded(>40 times),the polyQ segment of Ataxin-3 is extended,which leads to protein misfolding,aggregation,and formation of toxic inclusion body,driving the occurrence of SCA3.In addition,Ataxin-3 dysfunction is closely related to other NDDs:in AD,it promotes with abnormal aggregation of tau protein and oxidative stress;Ataxin-3 mutant aggravated the toxic aggregation of α-synuclein by interfering with the Parkin-mediated ubiquitin-proteasome pathway in PD.Ataxin-3 plays a neuroprotective role in ALS by hydrolyzating the K63 ubiquitin chain of SOD1 and promoting its autophagic clearance.This"duality"suggests that Ataxin-3 is both a causative agent of SCA3 and a potential therapeutic target for other NDDs.In the future,it is necessary to further analyze the molecular network of Ataxin-3 in NDDs and develop small molecule drugs or gene therapies targeting its functional regulation,so as to provide new strategies for precise intervention of NDDs.