Spinocerebellar ataxia type 3 (SCA3) belongs to the family of polyglutamine neurodegenerations. Each disorder stems from the abnormal lengthening of a glutamine repeat in a different protein. Although caused by a similar mutation, polyglutamine disorders are distinct, implicating non-polyglutamine regions of disease proteins as regulators of pathogenesis. SCA3 is caused by polyglutamine expansion in ataxin-3. To determine the role of ataxin-3’s non-polyglutamine domains in disease, we utilized a new, allelic series of Drosophila melanogaster. We found that ataxin-3 pathogenicity is saliently controlled by polyglutamine-adjacent ubiquitin-interacting motifs (UIMs) that enhance aggregation and toxicity. UIMs function by interacting with the heat shock protein, Hsc70-4, whose reduction diminishes ataxin-3 toxicity in a UIM-dependent manner. Hsc70-4 also enhances pathogenicity of other polyglutamine proteins. Our studies provide a unique insight into the impact of ataxin-3 domains in SCA3, identify Hsc70-4 as a SCA3 enhancer, and indicate pleiotropic effects from HSP70 chaperones, which are generally thought to suppress polyglutamine degeneration.

中文翻译：

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ataxin-3 的泛素相互作用基序通过 Hsc70-4 依赖性聚集调节其多聚谷氨酰胺毒性

脊髓小脑性共济失调 3 型 (SCA3) 属于多聚谷氨酰胺神经变性家族。每种疾病都源于不同蛋白质中谷氨酰胺重复序列的异常延长。尽管由相似的突变引起，但多聚谷氨酰胺疾病是不同的，这表明疾病蛋白质的非多聚谷氨酰胺区域是发病机制的调节剂。SCA3 是由 ataxin-3 中的多聚谷氨酰胺膨胀引起的。为了确定 ataxin-3 的非聚谷氨酰胺结构域在疾病中的作用，我们利用了一种新的等位基因系列黑腹果蝇。我们发现 ataxin-3 的致病性受到多聚谷氨酰胺相邻泛素相互作用基序 (UIM) 的显着控制，该基序可增强聚集和毒性。UIM 通过与热休克蛋白 Hsc70-4 相互作用而发挥作用，Hsc70-4 的减少以 UIM 依赖性方式降低了 ataxin-3 的毒性。Hsc70-4 还增强其他聚谷氨酰胺蛋白的致病性。我们的研究提供了对 ataxin-3 结构域在 SCA3 中的影响的独特见解，将 Hsc70-4 鉴定为 SCA3 增强子，并表明 HSP70 分子伴侣的多效作用，这通常被认为可以抑制聚谷氨酰胺变性。