CCK1受体激动剂调控mTOR通路在SCA3/MJD治疗中的作用研究

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a kind of highly heterogeneous neurodegenerative polyglutamine disease(polyQ disease) with poor prognosis. Due to its incompletely elucidated pathogenesis, there is no effective therapy. Some studies found the mTOR pathway could mediate the onset and progression of polyQ disease. In our previous study, we evaluated the treatment of CCK1 receptor agonist in SCA1 mouse model, suggesting that CCK1 receptor agonist could alleviate the behavior phenotype and pathology in SCA1 mouse. We will apply the UiPSCs of SCA3/MJD patient and related mouse model to explore the relationship between the CAG repeat number as well as phenotype and mTOR expression, and the investigate the modulation of mTOR pathway regulated by CCK1 receptor agonist in pathogenesis and treatment of SCA3/MJD. Our study is beneficial for better understanding of the role of CCK1 receptor agonist and mTOR pathway in SCA3/MJD, which will provide the new insights into precision medicine of polyQ disease.

脊髓小脑性共济失调3型/马查多-约瑟夫病(SCA3/MJD)是一种异质性高，预后差的神经退行性多聚谷氨酰胺病(polyQ病)，其发病机制尚未完全阐明，尚无有效治疗。研究发现，mTOR通路可能是polyQ病发生发展的重要调控媒介。前期工作中，我们探索了CCK1受体激动剂在SCA1小鼠模型中的治疗作用，发现其可通过激活mTOR通路改善小鼠的行为学及分子病理学指标。本研究拟在SCA3/MJD患者的尿源性诱导多能干细胞(UiPSCs)和SCA3/MJD转基因小鼠模型中，探讨mTOR表达水平与SCA3/MJD的CAG拷贝数及表型的相关性和在发病中的作用；并应用CCK1受体激动剂分别开展SCA3/MJD患者的UiPSCs及小鼠模型的治疗研究。这有助于阐明CCK1受体和mTOR通路在SCA3/MJD发病机制和治疗中的作用，为实现该类疾病的精准诊疗提供新线索。

脊髓小脑性共济失调3型/马查多-约瑟夫病(SCA3/MJD)是一种异质性高，预后差的神经退行性多聚谷氨酰胺病(polyQ病)，以选择性神经元死亡和核内包涵体形成为主要特征，其发病机制尚未完全阐明，尚无有效治疗。本项目前期研究发现，polyQ病之一的SCA1的mTOR表达下调，mTOR通路异常可能是polyQ病的重要发病机制。本项目聚焦mTOR在SCA3/MJD发病中的作用，应用SCA3/MJD的患者来源的iPSCs、皮肤成纤维细胞、转基因小鼠模型，检测并对比不同模型的mTOR表达水平，发现SCA3/MJD患者来源的iPSCs的mTOR表达水平较正常有上升趋势，而皮肤成纤维细胞和转基因小鼠模型的mTOR通路显著激活，与SCA1的mTOR下调表现不同，体现了polyQ病的高度异质性。在此基础上，本项目应用mTOR抑制剂雷帕霉素及Torin1，分别干预SCA3/MJD患者来源的皮肤成纤维细胞和转基因小鼠模型，发现两种药物均可降低SCA3/MJD皮肤成纤维细胞毒性蛋白ataxin-3的表达水平，减少核内包涵体数量，同时改善细胞活性，并改善SCA3/MJD转基因小鼠模型的分子病理及行为学表型。其中，雷帕霉素主要通过激活自噬发挥其治疗作用，Torin1还可能通过自噬以外的途径发挥其治疗作用，其治疗效果可能优于雷帕霉素，表明mTOR抑制剂对SCA3/MJD具有一定的治疗作用和临床应用前景。