Exercise-dependent mechanisms of protection in polyglutamine degeneration

多聚谷氨酰胺变性的运动依赖性保护机制

• 批准号: 10188094
• 负责人: Sokol Todi
• 金额: $ 42.35万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188094
• 关键词: Aging; Animal Model; Applications Grants; Ataxia; Atrophic; Automobile Driving; Biochemistry; Biological Models; Body part; CAG repeat; Cessation of life; Clinic; Data; Disease; Disease Progression; Disease model; Drosophila genus; Drosophila inturned protein; Drosophila melanogaster; Evaluation; Exercise; Family; Family member; Genes; Genetic; Health; Human; Huntington Disease; Impairment; Intervention; Investigation; Kennedy Syndrome; LY6E gene; Length; Longevity; MJD1 protein; Mediating; Modeling; Molecular; Movement; Nerve Degeneration; Nervous system structure; Neuronal Dysfunction; Organism; Pathology; Pathway interactions; Patients; Physiological; Process; Protein Biochemistry; Proteins; Research; Role; SCA2 protein; Spinocerebellar Ataxias; Symptoms; Textbooks; Therapeutic; Time; Trinucleotide Repeats; Type 1 Spinocerebellar Ataxia; Vertebrates; Wheelchairs; Work; age related; base; cell motility; design; endurance exercise; exercise training; experience; fighting; flexibility; fly; follow-up; improved; in vivo; insight; member; mimetics; nervous system disorder; neuroprotection; new therapeutic target; novel; polyglutamine; preservation; reduce symptoms

The central premise of this exploratory R21 application is to understand endurance exercise-dependent mechanisms protecting against polyglutamine (polyQ) neurodegeneration. Nine age-related neurological disorders are caused by abnormal expansion of the CAG triplet repeat of their respective genes. The elongated CAG repeat encodes an abnormally long polyQ tract that causes neuronal dysfunction and degeneration. These diseases constitute the polyQ family, which includes Spinocerebellar Ataxias (SCAs) 1, 2, 3, 6, 7 and 17, Huntington's Disease, Kennedy's Disease and Dentatorubral-pallidolyusian atrophy. Currently, there is no therapeutic solution for any member of the polyQ family; all patients lose their ability to control movement over time, invariably becoming wheelchair-bound and experiencing impaired control of other body parts as well. Endurance exercise is proven to ameliorate disease conditions in various disease models across species. We recently investigated the potential impact of exercise on loss of mobility in Drosophila melanogaster models of three polyQ disorders, SCA2, SCA3 and SCA6. We reasoned that using the fruit fly would provide expedient, in vivo information about conserved molecular pathways and mechanisms that, once characterized and understood, can be subsequently explored and expanded in vertebrates. Excitingly, we found that daily exercise significantly and markedly preserved mobility and endurance in aging SCA flies, indicating impaired disease progression. Based on additional results, we found that improved motility coincided with reduced disease protein levels. Through this proposal, we seek to expand on these promising observations through two aims that will explore the protective role of exercise across the spectrum of polyQ diseases, and will define molecular mechanisms that can be mobilized therapeutically in polyQ disease patients.

这个探索性的R21应用程序的中心前提是了解耐力运动依赖性 防止多聚谷氨酰胺（polyQ）神经变性的机制。9个与年龄相关的神经系统疾病 疾病是由其各自基因的CAG三联体重复的异常扩增引起的。细长 CAG重复序列编码异常长的polyQ束，导致神经元功能障碍和变性。这些 疾病构成polyQ家族，其包括脊髓小脑共济失调（SCA）1、2、3、6、7和17， 亨廷顿氏病、肯尼迪氏病和齿状核红核-苍白球神经萎缩。目前尚无 polyQ家族任何成员的治疗解决方案;所有患者都失去了控制运动的能力， 时间，总是成为轮椅和经验受损的控制其他身体部位以及。 耐力运动被证明可以改善各种疾病模型中的疾病状况。我们 最近研究了运动对黑腹果蝇模型运动能力丧失的潜在影响， 三种polyQ疾病SCA 2 SCA 3和SCA 6。我们推断，使用果蝇将提供权宜之计， 关于保守分子途径和机制的体内信息，一旦表征和理解， 可以随后在脊椎动物中探索和扩展。令人兴奋的是，我们发现每天锻炼 并且在老化的SCA果蝇中显著保留了活动性和耐力，表明疾病进展受损。 基于其他结果，我们发现运动性的改善与疾病蛋白水平的降低相一致。 通过这一提议，我们试图通过两个目标来扩展这些有希望的观测， 运动在polyQ疾病谱中的保护作用，并将定义可以 在polyQ疾病患者中进行治疗动员。