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.