Cell Signaling and Neurodegeneration

脊髓小脑性共济失调1型(SCA1)是9种致命性遗传性神经退行性疾病之一，由 框内CAG三核苷酸重复序列的扩增。每个重复序列编码一段谷氨酰胺残基 受影响的蛋白质，在SCA1的情况下，蛋白质是ataxin-1(ATXN1)。SCA1的症状包括 运动协调和平衡，说话含糊，吞咽困难，痉挛，以及一些认知 减损。SCA1病理的一个特征是浦肯野细胞的萎缩和最终的丧失。 小脑皮层。像许多神经退行性疾病一样，SCA1通常是一种起病较晚的疾病，提示 衰老引起的生理变化是疾病发生的原因之一。目前还没有有效的 治疗。因此，仍需确定SCA1发生和发展的信号通路和细胞介质。 这是寻找治疗方法的主要挑战，也是本申请中概述的研究的重点 持续的支持。这次竞争更新的主要目的是进一步检查ATXN1-S776的作用 通过检测改变ATXN1-S776磷酸化对多Qexp ATXN1毒性的影响 脑干-髓质，并表征了一种新的由CC1激活的保护通路 (Cock1R)激动剂在SCA浦肯野细胞中。

Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an in-frame CAG trinucleotide repeat. Each repeat tract encodes a stretch of glutamine residues in the affected protein, in the case of SCA1 the protein is ataxin-1 (ATXN1). Symptoms of SCA1 include loss of motor coordination and balance, slurred speech, swallowing difficulty, spasticity, and some cognitive impairment. A characteristic feature of SCA1 pathology is atrophy and eventual loss of Purkinje cells from the cerebellar cortex. Like many neurodegenerative disorders, SCA1 is typically a late onset disease suggesting that physiological changes due to aging contribute to the onset of the disease. There is currently no effective treatment. Thus, identifying signaling pathways and cellular mediators of SCA1 onset and progression remain a major challenge in the search for therapeutics and is the focus of the research outlined in this application for continued support. The major aims of this competitive renewal are to further examine the role of ATXN1-S776 phosphorylation by examining the impact of altering ATXN1-S776 phosphorylation on polyQexp ATXN1 toxicity the brainstem-medulla, and characterize a novel protective pathway activated by a cholecystokinin receptor 1 (Cck1R) agonist in SCA Purkinje cells.