Snijder Pauline M, Baratashvili Madina, Grzeschik Nicola A, Leuvenink Henri G D, Kuijpers Lucas, Huitema Sippie, Schaap Onno, Giepmans Ben N G, Kuipers Jeroen, Miljkovic Jan Lj, Mitrovic Aleksandra, Bos Eelke M, Szabó Csaba, Kampinga Harm H, Dijkers Pascale F, Bos Eelke M, Szabó Csaba, Kampinga Harm H, Dijkers Pascale F, Dunnen Wilfred F A den, Filipovic Milos R, Goor Harry van, Sibon Ody C M
Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Mol Med. 2016 Jan;21(1):758-768. doi: 10.2119/molmed.2015.00221. Epub 2015 Oct 13.
Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 () gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.
3型脊髓小脑共济失调（SCA3）是一种多聚谷氨酰胺（polyQ）疾病，由ataxin-3（）基因中的CAG重复扩增引起，导致毒性蛋白聚集。炎症和氧化应激被认为是导致这种神经退行性疾病进展的次要因素。目前尚无能够阻止或逆转SCA3进行性神经退行性变的治疗方法。在此我们表明，半胱氨酸代谢中的关键酶胱硫醚γ-裂解酶的过表达在SCA3模型中具有保护作用。SCA3果蝇表现出眼睛退化、氧化应激增加、不溶性蛋白聚集、蛋白质过硫化水平降低以及先天免疫反应激活增加。胱硫醚γ-裂解酶的过表达可恢复蛋白质过硫化、降低氧化应激、抑制免疫反应并改善与SCA3相关的组织退化。不溶性蛋白聚集水平未改变；因此，数据表明胱硫醚γ-裂解酶在改善蛋白质聚集的下游后果从而预防SCA3诱导的组织退化方面具有修饰作用。SCA3患者受影响的脑组织中胱硫醚γ-裂解酶表达降低，这表明胱硫醚γ-裂解酶表达或活性的增强剂是未来治疗的有吸引力候选物。
