Cell Signaling and Neurodegeneration

描述(申请人提供)：脊髓小脑性共济失调1型(SCA1)是九种致命的遗传性神经退行性疾病之一，由基础CAG三核苷酸重复序列扩张引起。每个重复序列在受影响的蛋白质中编码一段谷氨酰胺残基，在SCA1的情况下，蛋白质是ataxin-1(ATXN1)。SCA1的症状包括失去运动协调和平衡，说话含糊不清，吞咽困难，痉挛，以及一些认知障碍。SCA1病理的一个特征是小脑皮质浦肯野细胞的萎缩和最终的丢失。像许多神经退行性疾病一样，SCA1通常是一种起病晚的疾病，这表明衰老引起的生理变化有助于疾病的发生。目前还没有有效的治疗方法。因此，识别SCA1发生和发展的信号通路和细胞介质仍然是继续支持的应用。这次竞争性更新的主要目的是：1)在体内解剖调节小脑浦肯野细胞中ATXN1-S776磷酸化的信号通路(S)及其组件，以及2)评估S776及其磷酸化是否在突变型ATXN1诱导的疾病中除浦肯野细胞外的脑区起作用。最值得注意的是，由于脑干的病理，影响吞咽的球状体征

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is one of nine fatal inherited neurodegenerative diseases caused by expansion of an inframe 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 application for continued support. The major aims of this competitive renewal, are: 1) dissecting the signaling pathway(s) and their components that regulate phosphorylation of ATXN1-S776 in cerebellar Purkinje cells in vivo, and 2) assessing whether S776 and its phosphorylation plays a role in mutant ATXN1-induced disease in regions of the brain in addition to Purkinje cells. Most notably the Bulbar signs affecting swallowing, due to pathology in the brainstem