Understanding the Cellular Basis of Movement Disorders

了解运动障碍的细胞基础

• 批准号: 10630308
• 负责人: Puneet Opal
• 金额: $ 53.2万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630308
• 关键词: Ablation; Adult; Affect; Agonist; Alzheimer' s Disease; Astrocytes; Ataxia; Autopsy; Behavior assessment; Brain; CAG repeat; Cannabinoids; Cells; Cerebellar Cortex; Cerebellar degeneration; Cerebellum; Data; Defect; Development; Developmental Process; Disease; Disease Progression; Electrophysiology (science); Event; Functional disorder; Genetic; Genetic Transcription; Human; Huntington Disease; Impairment; Interneurons; Life; Modeling; Movement Disorders; Mus; Myoepithelial cell; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotransmitters; Parkinson Disease; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Play; Population; Process; Proliferating; Proteins; Purkinje Cells; Resistance; Role; Seizures; Sonic Hedgehog Pathway; Stimulation of Cell Proliferation; System; Testing; Therapeutic; Time; Toxic effect; Trinucleotide Repeat Expansion; Type 1 Spinocerebellar Ataxia; Wild Type Mouse; ataxin-1; autosome; behavior test; cyclopamine; endogenous cannabinoid system; experimental study; gain of function; gamma-Aminobutyric Acid; inhibitor; knock-down; mutant; network dysfunction; neuroprotection; overexpression; pharmacologic; polyglutamine; postnatal; preclinical trial; presynaptic; prevent; receptor; sonic hedgehog receptor; stellate cell; stem cell niche; stem cell population; stem cells; therapeutic target; transcriptomics; transmission process

Project Summary Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in ATXN1 that leads to an abnormally long polyglutamine tract in the subsequent protein, ataxin-1 (ATXN1). Mutant ATXN1 has a propensity to misfold, resist cellular degradation, and increase in toxicity as its levels rise. This toxicity occurs by a gain of function mechanism with evidence point to transcriptional derangements as an early, presymptomatic pathogenic event. We recently discovered that the earliest abnormalities in Purkinje cells (cells that are most vulnerable in SCA1) are not caused by cell- autonomous changes but in a non-cell autonomous manner by affecting the proliferation and fate of cerebellar post-natal stem cells. In this proposal, we will test the hypothesis that the underlying SCA1 pathology has its roots in early developmental processes and that if these defects are overcome one might be able to delay or ameliorate later neurodegeneration, thus paving the way for therapy for this currently untreatable condition.

项目总结