Cell Signaling and Neurodegeneration

脊髓小脑性共济失调1型（SCA 1）是由以下原因引起的九种致命的遗传性神经退行性疾病之一： 读框内CAG三核苷酸重复的扩增。每个重复序列编码一段谷氨酰胺残基， 受影响的蛋白质，在SCA 1的情况下，蛋白质是共济失调蛋白-1（ATXN 1）。SCA 1的症状包括： 运动协调和平衡，言语不清，吞咽困难，痉挛，和一些认知 损伤SCA 1病理学的一个特征性特征是来自小脑的浦肯野细胞的萎缩和最终损失。 小脑皮质与许多神经退行性疾病一样，SCA 1通常是一种迟发性疾病，表明 衰老引起的生理变化会导致疾病的发生。目前尚无有效 治疗因此，识别SCA 1发病和进展的信号通路和细胞介质仍然是一个重要的研究课题。 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， 继续支持。此次竞争性更新的主要目的是进一步研究ATXN 1-S776的作用 通过检查改变ATXN 1-S776磷酸化对polyQexp ATXN 1毒性的影响， 脑干-髓质，并描述了一种由胆囊收缩素受体1激活的新的保护途径 （Cck 1 R）激动剂在SCA浦肯野细胞中的作用。

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.