Cell Signaling and Neurodegeneration

描述（由申请人提供）：脊髓小脑共济失调1型（SCA 1）是由CAG三核苷酸重复序列扩增引起的9种致命性遗传性神经退行性疾病之一。每个重复序列编码受影响蛋白质中的一段谷氨酰胺残基，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的丧失、言语不清、吞咽困难、痉挛和一些认知障碍。SCA 1病理学的特征是小脑皮质浦肯野细胞的萎缩和最终丧失。像许多神经退行性疾病一样，SCA 1通常是一种迟发性疾病，表明由于衰老引起的生理变化有助于疾病的发作。目前尚无有效的治疗方法。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需要继续支持的应用程序。这种竞争性更新的主要目的是：1）剖析体内调节小脑浦肯野细胞中ATXN 1-S776磷酸化的信号传导途径及其组分，以及2）评估S776及其磷酸化是否在除浦肯野细胞之外的脑区域中的突变体ATXN 1诱导的疾病中起作用。由于脑干病变，最明显的是影响吞咽的延髓体征

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