P55 Overexpression of cystathionine gamma-lyase supresses spinocerebellar ataxia type 3-associated neurodegeneration in drosophila

Abstract

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the ataxin3 gene resulting (amongst others) in toxic protein aggregation. Inflammation and oxidative stress are secondary factors contributing to the progression of the disease. There is no cure that halts or reverses the symptoms of SCA3. The transsulfuration pathway has been implicated in diverse crucial physiological processes, among which are those in the central nervous system. Activation of this pathway leads to biosynthesis of hydrogen sulfide (H 2 S), which is produced by cystathionine gamma-lyase (CSE), cystathionine beta-synthase and 3-mercaptopyruvate sulfurtransferase. This gas has anti-oxidative and anti-inflammatory properties, making it an attractive candidate to intervene in damaging processes of SCA3. Here, we show that overexpression of the H 2 S-producing enzyme, CSE, suppresses SCA3-associated degeneration in Drosophila . This decrease in degeneration is associated with reduced oxidative stress and a dampened immune response. Treatment of SCA3-bearing flies with an H 2 S donor, sodium thiosulfate, resulted in similar protective effects, suggesting that the beneficial effects of CSE overexpression are due to an increased production of H 2 S. In humans, we observed expression of CSE in SCA3-relevant brain regions and a decreased CSE expression in brains of SCA3 patients. Our data implicate a modifying role of the CSE/H 2 S axis in SCA3-induced tissue degeneration.