Determining if there is a primary myopathy in Huntington's disease

确定亨廷顿病是否存在原发性肌病

• 批准号: 9516305
• 负责人: Andrew Alvin Voss
• 金额: $ 45.5万
• 依托单位: WRIGHT STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9516305
• 关键词: Address; Automobile Driving; Biological Markers; Bradykinesia; Brain imaging; CAG repeat; Chloride Channels; Clinical; Cognitive deficits; Defect; Denervation; Depressed mood; Development; Disease; Disease Progression; Dystonia; Event; Generations; Genes; Genetic Diseases; Huntington Disease; Huntington gene; Ion Channel; Length; Measures; Messenger RNA; Modeling; Molecular; Monitor; Motor; Mus; Muscle; Muscle relaxation phase; Mutate; Myopathy; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathology; Patients; Peripheral; Potassium; RNA Splicing; Role; Signal Transduction; Skeletal Muscle; Symptoms; Testing; Time; Tissues; Transgenic Organisms; Translating; Trinucleotide Repeats; loss of function; motor symptom; mouse model; mutant; neuromuscular; neuromuscular examination; neuromuscular system; neuromuscular transmission; new therapeutic target; novel therapeutics; postnatal; presynaptic; response; synaptic function; targeted biomarker; therapeutic target; transmission process; voltage clamp

PROJECT SUMMARY Huntington’s disease (HD) is a progressive genetic disorder with devastating motor and cognitive defects and no therapies to stop or reverse the disease. Monitoring disease progression relies on brain imaging over several months to observe degeneration. Thus, our long-term objective is to identify new peripheral therapeutic targets and biomarkers of HD progression that are easy to access and simple to interpret. Understanding of basic pathophysiological mechanisms in peripheral tissues, such as skeletal muscle, would provide new opportunities for HD therapy and accessible biomarkers. Although classically categorized as a neurodegenerative disease, Both HD patients and mouse models present with debilitating muscle pathology. We previously discovered a loss-of-function in the muscle chloride channel (ClC-1) and inwardly rectifying potassium (Kir) channel in skeletal muscle from transgenic R6/2 Huntington’s disease mice, both contributing to muscle hyperexcitability. The hyperexcitability could help explain rigidity, dystonia, delayed muscle relaxations, and bradykinesia in the disease. We have also shown depressed neuromuscular transmission in late-stage R6/2 mice, which could help explain the motor impersistence in Huntington’s patients. That we found no evidence of denervation supports the possibility that these defects are due to mutant huntingtin expression in muscle. Moreover, the depressed transmission appears to compensate for the muscle hyperexcitability in late- stage R6/2 mice. Therefore, we hypothesis that primary defects in Huntington’s disease skeletal muscle result in compensatory decreases in neuromuscular transmission and motor impersistence. To examine the role of depressed neuromuscular transmission and/or muscle defects in Huntington’s motor symptoms, we will measure force generation in response to nerve and direct muscle stimulation (Aim 1). To assess the role of signaling between nerve and muscle during disease progression, we will compare the time course over which the neuromuscular defects develop to the time course of muscle defects (Aim 2). By developing and examining a muscle-only model of Huntington’s disease, we will determine the role of a primary myopathy in driving muscle and neuromuscular defects (Aim 3). Successfully completing these aims will provide the most complete characterization of general synaptic function in HD to date and further support they hypothesis that HD is also a primary myopathy. By examining the relationship between the muscle and neuromuscular defects in R6/2 mice we will begin to define the role of neuronal and muscle defects in the motor symptoms. Finally, the defects we identify could be targeted by novel therapeutics and will quickly translate to the development of needed peripheral biomarkers of disease progression with collaborators.

项目摘要 亨廷顿氏病（HD）是一种进行性遗传疾病，具有破坏性的运动和认知缺陷， 没有治疗方法来阻止或逆转这种疾病。监测疾病进展依赖于大脑成像， 几个月来观察退化。因此，我们的长期目标是确定新的外周治疗药物， HD进展的靶点和生物标志物，易于获取和解释。了解 外周组织如骨骼肌的基本病理生理机制，将提供新的 HD治疗的机会和可获得的生物标志物。虽然经典分类为 HD患者和小鼠模型均表现出衰弱性肌肉病理学。 我们以前发现肌肉氯离子通道（ClC-1）和内向整流通道（ClC-1）功能丧失， 转基因R6/2亨廷顿病小鼠骨骼肌中的钾（Kir）通道，两者都有助于 肌肉过度兴奋兴奋过度可以解释僵硬，肌张力障碍，肌肉松弛延迟， 和运动迟缓。我们还发现，在晚期， R6/2小鼠，这可能有助于解释亨廷顿病患者的运动不持久性。我们发现没有 去神经支配的证据支持这些缺陷是由于突变的亨廷顿蛋白表达的可能性， 肌肉.此外，抑制的传输似乎补偿了晚期的肌肉过度兴奋， R6/2期小鼠。因此，我们假设亨廷顿病骨骼肌的原发性缺陷 导致神经肌肉传递的代偿性降低和运动不持久。到 检查神经肌肉传递抑制和/或肌肉缺陷在亨廷顿运动中的作用 症状，我们将测量响应于神经和直接肌肉刺激的力生成（目标1）。到 为了评估神经和肌肉之间的信号传导在疾病进展中的作用，我们将比较 神经肌肉缺陷发展到肌肉缺陷的时间过程（目的2）。通过 开发和检查亨廷顿病的肌肉模型，我们将确定一个 驱动肌原发性肌病和神经肌肉缺陷（目的3）。成功实现这些目标 将提供迄今为止HD中一般突触功能的最完整表征，并进一步支持 他们假设HD也是一种原发性肌病。通过检查肌肉和 我们将开始确定神经元和肌肉缺陷在R6/2小鼠中的作用， 运动症状最后，我们发现的缺陷可以被新的治疗方法所针对，并将很快 转化为与合作者开发疾病进展所需的外周生物标志物。

项目成果

The mechanism underlying transient weakness in myotonia congenita.

• DOI: 10.7554/elife.65691
• 发表时间: 2021-04-27
• 期刊: eLife
• 影响因子: 7.7
• 作者: Myers JH;Denman K;DuPont C;Hawash AA;Novak KR;Koesters A;Grabner M;Dayal A;Voss AA;Rich MM
• 通讯作者: Rich MM

Mechanisms of altered skeletal muscle action potentials in the R6/2 mouse model of Huntington's disease.

亨廷顿病 R6/2 小鼠模型中骨骼肌动作电位改变的机制。

• DOI: 10.1152/ajpcell.00153.2020
• 发表时间: 2020
• 期刊: American journal of physiology. Cell physiology
• 作者: Miranda,DanielR;Reed,Eric;Jama,Abdulrahman;Bottomley,Michael;Ren,Hongmei;Rich,MarkM;Voss,AndrewA
• 通讯作者: Voss,AndrewA

The role of action potential changes in depolarization-induced failure of excitation contraction coupling in mouse skeletal muscle.

• DOI: 10.7554/elife.71588
• 发表时间: 2022-01-05
• 期刊: eLife
• 影响因子: 7.7
• 作者: Wang X;Nawaz M;DuPont C;Myers JH;Burke SR;Bannister RA;Foy BD;Voss AA;Rich MM
• 通讯作者: Rich MM

Acetylcholine receptor subunit expression in Huntington's disease mouse muscle.

• DOI: 10.1016/j.bbrep.2021.101182
• 发表时间: 2021-12
• 期刊: Biochemistry and biophysics reports
• 影响因子: 2.7
• 作者: Simpson B;Rich MM;Voss AA;Talmadge RJ
• 通讯作者: Talmadge RJ

A mouse model of Huntington's disease shows altered ultrastructure of transverse tubules in skeletal muscle fibers.

• DOI: 10.1085/jgp.202012637
• 发表时间: 2021-04-05
• 期刊: The Journal of general physiology
• 作者: Romer SH;Metzger S;Peraza K;Wright MC;Jobe DS;Song LS;Rich MM;Foy BD;Talmadge RJ;Voss AA
• 通讯作者: Voss AA