MOTOR NEURON DISEASE-NEUROPHYSIOLOGY AND PATHOLOGY

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。虽然很多努力都集中在理解运动神经元在MND中死亡的原因，但很少有人关注运动终端在运动单元功能障碍发病机制中的可能作用。在犬类MND（遗传性犬脊髓性肌萎缩症，HCSMA）中，我们已经证明运动单元功能的丧失发生在神经肌肉连接处（NMJ），其机制损害突触传递，但不涉及运动终端或轴突的可检测变性，因此，在HCSMA中。在美国，运动单元功能的丧失甚至先于周围的退化。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。我们的第一个目标将是确认初步数据，即在SOD1转基因小鼠脊髓中，肌肉的广泛去神经支配先于运动神经元细胞死亡的发生。在另一个目标中，我们将收集证据来支持一种与钙处理能力下降有关的NMJ变性背后的兴奋性毒性的观点。我们获得的初步数据表明，SOD1小鼠的NMJ变性不仅仅是突触前丢失的问题，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。我们将检验这些观察提出的几个假设。在另一项研究中，我们将确定已知存在并作用于运动终末（calpain）的钙活化蛋白酶拮抗剂是否能抑制SOD1小鼠的NMJ变性。这项工作的结果将确定SOD1转基因MND小鼠模型中运动单元功能的丧失是否由于运动终端功能障碍而发生。

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.