Motor axon development in a zebrafish model of Charcot-Marie-Tooth disease

腓骨肌萎缩症斑马鱼模型运动轴突的发育

• 批准号: 7516562
• 负责人: Lara Diane Hutson
• 金额: $ 22.01万
• 依托单位: WILLIAMS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516562
• 关键词: Actins; Address; Adolescence; Adult; Affect; Afferent Neurons; Architecture; Atrophic; Axon; Biological; Biological Assay; Biological Models; Cell Death Signaling Process; Cells; Characteristics; Charcot-Marie-Tooth Disease; Cultured Cells; Defect; Deformity; Depth; Development; Disease; Disease Management; Disease Progression; Disruption; Distal; Environment; Environmental Risk Factor; Etiology; Event; Exercise; Failure; Family; Genes; Genetic; Goals; HSPB1 gene; Health Care Costs; Heat shock proteins; Heterogeneity; Human; Individual; Inherited; Intermediate Filament Proteins; Intermediate Filaments; Lead; Life; Maintenance; Modeling; Molecular Chaperones; Monozygotic twins; Motor; Muscle; Muscle Weakness; Muscular Atrophy; Mutation; Neurodegenerative Disorders; Neuromuscular Diseases; Neurons; Neuropathy; Numbness; Organism; Oxidation-Reduction; Pathology; Patients; Penetrance; Physiological; Prevalence; Prevention; Progressive Disease; Public Health; Quality of life; Reconstructive Surgical Procedures; Reporting; Research; Role; Sensory; Severities; Skeletal system; Strenuous Exercise; Stress; Symptoms; Tendon Reflex; Testing; Toxic effect; Variant; Walking; Zebrafish; bone; design; disability; environmental stressor; improved; infancy; nervous system development; prevent; protein aggregate; protein aggregation; response

DESCRIPTION (provided by applicant): Charcot-Marie-Tooth disease (CMT), the most common inherited neuromuscular disorder, is a progressive disease characterized by degeneration of long motor and sensory axons, resulting in muscle atrophy and long-term disability. Distal hereditary motor neuropathy (dHMN) is a very closely-related disease characterized by motor, but not sensory, axon degeneration. These diseases usually show dominant inheritance, with symptoms first appearing during the second or third decade of life. Mutations in any one of several genes are known to cause either or both diseases. For example, mutations in the small heat shock proteins (sHSPs) HSP27 or HSPB8 can cause either CMT or dHMN. sHSPs are well known for their roles in protecting cells from the effects of environmental stressors and for regulating actin and intermediate filament dynamics. Misexpressing the disease-causing variants of HSP27 in cultured cells results in aggregation of intermediate filament proteins, suggesting that the axonal degeneration characteristic of CMT and dHMN may be due to either the sequestration of intermediate filaments and subsequent failure to appropriately establish or maintain axon architecture, or toxicity of protein aggregates. Understanding the etiology of these diseases is complicated by the large degree of heterogeneity within families -- and between at least two identical twins -- suggesting that environmental and/or multiple genetic factors may contribute to disease progression. Finally, while the mutations are assumed to act autonomously within neurons, HSP27 is expressed in developing muscle and it is upregulated in adult muscle in response to physiologic stress. Using zebrafish as a model system, we propose to determine (1) how HSP27 disease mutations affect the development and maintenance of motor axons, (2) whether the mutations sensitize axons to the effects of environmental stress, and (3) whether HSP27 is required in neurons, muscle, or both. In order to accomplish these objectives, we will misexpress zebrafish versions of the HSP27 disease variants (all of which act dominantly) in the zebrafish, either ubiquitously or in neurons or muscle and assay the effects on the development and maintenance of motor axon architecture and protein aggregation. The results of these studies will help us to better understand the cell biological events leading to axon degeneration in CMT and dHMN. Furthermore, since the progression and severity of CMT and dHMN are likely determined, at least in part, by environmental factors, the results of these studies could have direct implications for the prevention and management of these diseases. PUBLIC HEALTH RELEVANCE This research outlined in this proposal is designed to address how mutations in the small heat shock protein Hsp27 cause two neurodegenerative diseases, Charcot-Marie-Tooth Disease and Distal Hereditary Motor Neuropathy and to test whether environmental stress contributes to their development or progression. The results of these studies could significantly impact our ability to prevent or slow progression of the diseases, thus improving the quality of life of these patients as well as reducing health care costs associated with treating their symptoms.

描述（由申请人提供）：最常见的遗传性神经肌肉疾病是charcot-marie-marie-tooth病（CMT），是一种进行性疾病，其特征是长运动和感觉轴突退化，导致肌肉萎缩和长期残疾。遗传性运动神经病（DHMN）是一种非常紧密的疾病，其特征是运动，但不是感觉的轴突变性。这些疾病通常显示出主导的遗传，症状首先出现在生命的第二或第三十年中。已知几种基因中的任何一个中的突变都会引起或两种疾病。例如，小热激蛋白（SHSP）HSP27或HSPB8中的突变会导致CMT或DHMN。 SHSP以保护细胞免受环境压力源的影响以及调节肌动蛋白和中间丝动力学的作用而闻名。在培养细胞中，HSP27引起疾病的变体导致中间细丝蛋白的聚集，这表明CMT和DHMN的轴突变性特征可能是由于中间丝的序列造成的，并且随后的失败无法适当地建立或维持轴突结构或维持轴突结构或蛋白质的毒性。理解这些疾病的病因是家庭内部以及至少两个相同的双胞胎之间的巨大异质性的复杂性，这表明环境和/或多种遗传因素可能导致疾病进展。最后，尽管假定突变在神经元中自主作用，但HSP27在发育中表达，并且在成年肌肉中响应生理压力而在成年肌肉中上调。我们建议使用斑马鱼作为模型系统，以确定（1）HSP27疾病突变如何影响运动轴突的发育和维持，（2）突变是否使轴突对环境压力的影响敏感，以及（3）在神经元，肌肉还是两者中都需要HSP27。为了实现这些目标，我们将在斑马鱼中或神经元或肌肉中使用HSP27疾病变体的斑马鱼版本（所有这些作用），并分析对运动轴突结构和蛋白质聚集的影响。这些研究的结果将有助于我们更好地了解导致CMT和DHMN轴突变性的细胞生物学事件。此外，由于CMT和DHMN的进展和严重程度至少部分地由环境因素确定，因此这些研究的结果可能对预防和管理这些疾病具有直接影响。该提案中概述的这项研究旨在解决小型热休克蛋白HSP27中的突变如何引起两种神经退行性疾病，charcot-marie-tooth病和遗传性运动神经病远端以及测试环境压力是否有助于其发育或进展是否有助于其发育或进展。这些研究的结果可能会极大地影响我们预防或减缓疾病进展的能力，从而改善这些患者的生活质量，并降低与治疗症状相关的医疗保健费用。