Functional Study Of The Spinocerebellar Ataxia-related Gene Atx-3in C. Elegans

Background:Spinocerebellar ataxia (SCA) is a highly heterogeneous group of progressive neurodegenerative diseases characterized by gait ataxia. To date, genetic studies have identified at least20causative genes for SCAs. How these genes function in the pathogenesis of SCAs is still unclear. SCA3(also known as Machado-Joseph disease) is the most common SCA worldwide, which is primarily caused by the expansion of a polyQ stretch in the ataxin-3protein. To further understand the function of ataxin-3, we investigated how atx-3(the C. elegans ortholog of ataxin-3) affects lifespan and stress resistance in C. elegans and interacts with the insulin-insulin-like growth factor1(IGF-1) signaling pathway.Methods:We generated chn-1(by155); atx-3(gk193) double mutants (chn-1is C. elegans ortholog of carboxyl terminus of Hsc-70-interacting protein, mutations in which cause autosomal recessive cerebellar ataxia.) and analyzed the lifespans and locomotion of N2, chn-1(by155), atx-3(gk193), chn-1(by155);atx-3(gk193) at20℃and35℃. We also analyzed how chn-1and atx-3interact with the insulin-like pathway genes daf-2and daf-16to affect lifespans and locomotion under heat shock. Results:We found that there is no significant difference in the lifespans and locomotion among N2, chn-1(by155), atx-3(gk193), chn-1(by155);atx-3(gk193) at20℃. Under heat shock, chn-1(by155) mutants had a reduced lifespan and impaired locomotion, and atx-3(lf) could increase the lifespan and locomotion of chn-1(lf) mutants. Under heat shock, daf-2(lf) could enhance the lifespan and locomotion of chn-1(lf), atx-3(lf) and chn-1(lf);atx-3(lf) mutants, while daf-16(lf) could suppress the extended lifespan and improved locomotion of atx-3(lj) and chn-1(lf);atx-3(lf) mutants, but did not affect chn-1(lf) mutants.Conclusions:chn-1(lf) causes a lifespan reduction and impaired locomotion under heat shock, and atx-3(lf) could suppress heat shock-induced defects of chn-1(lf) mutants. Genetic analyses suggest that the insulin-insulin-like growth factor1(IGF-1) signaling pathway might mediate the effects of atx-3and chn-1on C. elegans lifespan and locomotion. Therefore cerebellar ataxia caused by mutations in ataxin-3and CHIP might be linked to the activity of the IIS pathway.