南京医科大学学报（自然科学版）2026，Vol.46Issue(4)：512-519,8.DOI:10.7655/NYDXBNSN251358
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
Research progress on the role of Ataxin-3 mediated protein homeostasis disruption in neurodegenerative diseases
摘要
Abstract
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.关键词
Ataxin-3/神经退行性疾病/去泛素化/蛋白质稳态/神经炎症Key words
Ataxin-3/neurodegenerative disease/deubiquitination/protein homeostasis/neuroinflammation分类
医药卫生引用本文复制引用
范雪,谢鹏宇,侯霞..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[J].南京医科大学学报（自然科学版）,2026,46(4):512-519,8.基金项目
黑龙江省自然科学基金(LH2020H003) （LH2020H003）
黑龙江省省属高等学校基本科研业务费科研项目(2023-KYYWF-0596) （2023-KYYWF-0596）
佳木斯大学"东极"学术团队建设(DJXSTD202403) （DJXSTD202403）
