Anti-oxidative Effects Of Ataxin-3

Polyglutamine neurodegenerative diseases are caused by the expansion of an unstable CAG trinucleotide repeat such that the repeat is translated into a stretch of glutamine residues. At present, the polyglutamine diseases are the most common form of inherited neurodegenerative diseases. The polyglutamine diseases include the Huntington disease (HD), spinocerebellar ataxias (SCA1-3,6,7et al), spinobulbar muscular atrophy (SBMA) and dentatorubropallidoluysian atrophy (DRPLA) et al. The Spinocerebellar ataxia type3(SCA3)/Machado-Joseph disease (MJD) is the most frequent form among the inherited cerebellar ataxias.SCA3/MJD neuronal loss is most prominent in the basal ganglia, brain stem, and spinal cord. Which leads the patients to have spasticity, hyperreflexia, nystagmus, swallowing difficulties, and Babinski sighs et al. The SCA3/MJD is caused by a CAG-trinucleotide expansion in the disease-associated gene ATXN3encoded ataxin-3protein with a polyglutamine expansion.The ataxin-3knockout C. elegans and mice have no major abnormalities. However, the findings early suggested that ataxin-3may have a neuroprotective function. Interestingly, the studies found that pathogenic ataxin-3affected Bcl-XL and Bax mRNA levels, and impair anti-oxidative stress system. But the physiological involvement of ataxin-3in oxidative stress remains unknown.In our study, we explore the potential role of ataxin-3in oxidative stress. We find that ataxin-3plays a protective role against H2O2-induced oxidative stress in a Bcl-XL-dependent manner. Our results show that ataxin-3can directly interact with Bcl-XL, and the precise domains required for the interaction is the N-terminus of ataxin-3and the C-terminus of Bcl-XL.Ataxin-3promotes the interaction between Bcl-XL and Bax, but does not affect the degradation of Bcl-XL and Bax.Ataxin-3binds to Bcl-XL and enhances the interaction between Bcl-XL and Bax, but it does not bind to Bax. So, we indicate ataxin-3recruits Bcl-XL, subsequently Bax, to a protein-interacting complex, and then promotes the interaction between Bcl-XL and Bax in cells. We hypothesize that ataxin-3may cause a conformational change of Bcl-XL protein after it interacts with Bcl-XL, thereby somehow enhances the association between Bcl-XL and Bax.We further checked whether pathogenic polyQ-expanded ataxin-3could bind to Bcl-XL similarly as WT ataxin-3does. Our results indicate that WT and pathogenic polyQ-expanded ataxin-3displayed no difference in binding to Bcl-XL directly in vitro. We suggest that the directly interaction between ataxin-3and Bcl-XL is polyQ-length independent, and the interactions between Bcl-XL and Bax aren’t modulated by the length of polyQ tract in ataxin-3in vitro.These results indentify ataxin-3as a novel against oxidative stress protein in cells and suggest that ataxin-3plays an important role in oxidative stress involved in SCA3/MJD. So, that SCA3/MJD disease protein ataxin-3functions as a novel anti-oxidative regulator in cooperation with mitochondrial Bcl-2family proteins under oxidative stress conditions.