PolyQ扩增突变的Ataxin-3通过调控PPARδ参与脊髓小脑共济失调3型的分子机制研究

脊髓小脑共济失调3型（SCA3）是最常见的神经遗传变性疾病之一，探讨其机制意义重大。PPARδ是近年发现的PPAR新亚型，在神经系统疾病中研究尚少。我们前期发现PPARδ在小脑中含量丰富，对线粒体及能量生成影响巨大。最近我们发现PPARδ在由Ataxin-3的PolyQ扩增突变所致的SCA3中明显降低，但具体机制不明。既往研究显示：PolyQ扩增突变的Ataxin-3能够通过转录或相互作用异常影响多种蛋白的含量及功能。我们推测：PolyQ突变的Ataxin-3通过干扰或相互作用异常影响PPARδ的功能及线粒体产生，参与SCA3的发生。本课题组已繁育SCA3转基因小鼠，完成SCA3患者来源的iPSC重编程并能够诱导分化为神经元。本研究拟应用上述疾病模型，从分子、细胞、动物等多层次探讨PolyQ突变型Ataxin-3调控PPARδ参与SCA3的可能分子机制，为阐明SCA3的发病机制提供新思路。

Spinocerebellar ataxia type 3 (SCA3) is one of the most common neurodegenerative disorders. Further exploration of pathogenesis underlying SCA3 is of great significance. PPARδ was discovered in recent years as one subtype of PPARs, which was lack of investigation in neurological diseases. Currently, our group reported that PPARδ was superiorly abundant in brains of wild mice and played an important role in regulating energy production, while in SCA3 disease model caused by PolyQ expansion of Ataxin-3 our preliminary work found PPARδ was significantly reduced. However, the specific molecular mechanism remains unclear. Moreover, it is reported that PolyQ expansion Ataxin-3 affects the expression and function of many proteins through abnormal transcription or interaction. Based on the above results, we hypothesize that PolyQ expansion Ataxin-3 affects the function of mitochondria by regulating PPARδ, and then participates in the occurrence of SCA3. Our group has established the SCA3 transgenic mice and completed the identification and breeding, as well as patient-derived iPSC reprogramming and neurons induction. The current study aims to apply the above disease models from molecular, cellular and animal aspects to explore the possible mechanisms of PolyQ expansion Ataxin-3 via regulating PPARδ in SCA3. This study will provide novel ideas for further elucidating the mechanisms of SCA3.