MOTOR NEURON DISEASE-NEUROPHYSIOLOGY AND PATHOLOGY

运动神经元疾病-神经生理学和病理学

• 批准号: 6668670
• 负责人: Martin J Pinter
• 金额: $ 28.88万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668670
• 关键词: calcium channel; calcium ion; calpain; cell death; cellular pathology; degenerative motor system disease; electromyography; electrophysiology; enzyme inhibitors; genetic disorder; genetically modified animals; immunocytochemistry; laboratory mouse; molecular pathology; motor neurons; muscle; neurofilament; neuromuscular junction; neuromuscular transmission; neurophysiology; neurotransmitter transport; pathologic process; progressive spinal muscular atrophy; superoxide dismutase; synapses

DESCRIPTION (provided by applicant): Our understanding of mechanisms that contribute to the pathogenesis of motor neuron disease (MND) remains incomplete. While much effort has been focused on understanding why motor neurons die in MND, little attention has been paid to the possible role of the motor terminal in the pathogenesis of motor unit dysfunction. In a canine version of MND (Hereditary Canine Spinal Muscular Atrophy, HCSMA), we have demonstrated that loss of motor unit function occurs at the neuromuscular junction (NMJ) by mechanisms that compromise synaptic transmission but do not involve detectable degeneration of the motor terminal or axon, Thus, in HCSMA., loss of motor unit function precedes even degeneration in the periphery. We do not know whether these phenomena are specific for HCSMA. Thus, one goal of the present work will be to extend the type of analysis we have performed in HCSMA to another model of MND, the SOD1 transgenic mouse. Our first Aim will be to confirm preliminary data that extensive denervation of muscle precedes the onset of motor neuron cell death in the spinal cord of SOD1 transgenic mice. In another aim, we will collect evidence to support the idea that a version of excitotoxicity underlies NMJ degeneration that is related to decreased calcium handling capacity. Preliminary data we have obtained indicate that NMJ degeneration in SOD1 mice is not simply a matter of presynaptic loss but may reflect an interactive process with muscle that may require muscle fiber activity and resembles in many ways the process of NMJ synapse elimination observed during normal postnatal development. We will test several hypotheses suggested by these observations. In another study, we will determine whether antagonists for calcium-activated proteases known to exist and operate in motor terminals (calpains) can inhibit NMJ degeneration in SOD1 mice. The results of this work will determine whether loss of motor unit function in the SOD1 transgenic mouse model of MND occurs as a result of motor terminal dysfunction.

描述（由申请人提供）：我们对运动神经元疾病（MND）发病机制的理解仍然不完整。尽管人们付出了很多努力来理解为什么运动神经元在 MND 中死亡，但很少有人关注运动末梢在运动单位功能障碍的发病机制中可能发挥的作用。在犬类 MND（遗传性犬脊髓性肌萎缩症，HCSMA）中，我们证明了运动单位功能的丧失发生在神经肌肉接头（NMJ），其机制损害了突触传递，但不涉及可检测到的运动末梢或轴突的退化。因此，在 HCSMA 中，运动单位功能的丧失甚至先于外周的退化。我们不知道这些现象是否是 HCSMA 特有的。因此，目前工作的一个目标是将我们在 HCSMA 中进行的分析类型扩展到另一种 MND 模型，即 SOD1 转基因小鼠。我们的第一个目标是确认初步数据，即 SOD1 转基因小鼠脊髓中运动神经元细胞死亡之前发生广泛的肌肉去神经支配。在另一个目标中，我们将收集证据来支持这样一种观点，即兴奋性毒性是 NMJ 退化的基础，而 NMJ 退化与钙处理能力下降有关。我们获得的初步数据表明，SOD1 小鼠的 NMJ 退化不仅仅是突触前损失的问题，而且可能反映了与肌肉的相互作用过程，可能需要肌纤维活动，并且在许多方面类似于正常出生后发育过程中观察到的 NMJ 突触消除过程。我们将测试这些观察结果提出的几个假设。在另一项研究中，我们将确定已知存在并在运动末梢（钙蛋白酶）中起作用的钙激活蛋白酶的拮抗剂是否可以抑制 SOD1 小鼠的 NMJ 变性。这项工作的结果将确定 SOD1 转基因 MND 小鼠模型中运动单位功能的丧失是否是由于运动末梢功能障碍而发生的。