Molecular genetics of neurodegenerative pathogenic and protective pathways: The SCA1 perspective

神经退行性病变致病和保护途径的分子遗传学：SCA1 视角

• 批准号: 10614029
• 负责人: Harry T. Orr
• 金额: $ 84.87万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2030-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614029
• 关键词: Affect; Aging; Ataxia; Atrophic; Brain Stem; Brain region; CAG repeat; Cerebellar Cortex; Cerebellum; Characteristics; Cholecystokinin; Deglutition; Equilibrium; Glutamine; Impaired cognition; Inherited; Knock-in; Late-Onset Disorder; LoxP-flanked allele; Mediator; Molecular; Molecular Genetics; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Onset of illness; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Phenotype; Physiological; Proteins; Purkinje Cells; Research; Signal Pathway; Speech; Stretching; Symptoms; Therapeutic; Tissues; Type 1 Spinocerebellar Ataxia; ataxin-1; cell type; effective therapy; mouse model; protective pathway; spasticity; therapeutic target

Project Summary 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. Identifying signaling pathways and cellular mediators of SCA1 pathogenesis in the cerebellum leading to ataxia and in the brainstem that underlie lethality are critical in the search for therapeutics and are the focus of the research outlined in this application for continued support.

项目摘要 脊髓小脑性共济失调1型（SCA 1）是九种致命的遗传性神经退行性疾病之一， 由CAG三核苷酸重复序列扩增引起的疾病。每个重复道 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， ATXN1（ataxin-1）SCA 1的症状包括运动协调性丧失， 平衡，言语不清，吞咽困难，痉挛和一些认知障碍。 SCA 1病理学的特征是浦肯野细胞的萎缩和最终丧失 从小脑皮层像许多神经退行性疾病一样，SCA 1通常是一种神经退行性疾病。 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。目前没有有效的治疗方法。识别信令 小脑中SCA 1发病机制的通路和细胞介质导致 共济失调和脑干中的致命性是寻找 治疗，并且是本申请中概述的研究的重点， 支持.