Cell Signaling and Neurodegeneration

描述（由申请人提供）：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，由框架内CAG三核苷酸重复扩增引起。每个重复通道编码受影响蛋白中的一段谷氨酰胺残基，在SCA1的情况下，该蛋白是ataxin-1 （ATXN1）。SCA1的症状包括运动协调和平衡丧失、言语不清、吞咽困难、痉挛和一些认知障碍。SCA1病理的一个特征是小脑皮层的浦肯野细胞萎缩和最终丢失。与许多神经退行性疾病一样，SCA1是一种典型的晚发性疾病，表明衰老引起的生理变化有助于疾病的发病。目前尚无有效的治疗方法。因此，识别SCA1发生和进展的信号通路和细胞介质仍然是一个持续支持的应用。这种竞争性更新的主要目的是：1)在体内解剖小脑浦肯野细胞中调节ATXN1-S776磷酸化的信号通路及其组分，以及2)评估S776及其磷酸化是否在除浦肯野细胞外的大脑区域突变atxn1诱导的疾病中起作用。最明显的是影响吞咽的球征，这是由于脑干的病理

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