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）发病机制的理解仍不完整。虽然许多努力都集中在了解为什么运动神经元死亡的MND，很少有人注意到运动终端的运动单位功能障碍的发病机制中可能发挥的作用。在MND（遗传性犬脊髓性肌萎缩症，HCSMA）的犬版本中，我们已经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，但不涉及运动终末或轴突的可检测变性。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，本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，即在SOD 1转基因小鼠脊髓中运动神经元细胞死亡开始之前，肌肉的广泛去神经支配。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变性的基础，与钙处理能力降低有关。我们已经获得的初步数据表明，在SOD1小鼠的NMJ退化不仅仅是一个突触前损失的问题，但可能反映了一个相互作用的过程，肌肉可能需要肌纤维的活动，并在许多方面类似于正常的出生后发育过程中观察到的NMJ突触消除的过程。我们将检验这些观察所提出的几个假设。在另一项研究中，我们将确定已知存在并在运动终末（钙蛋白酶）中工作的钙激活蛋白酶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运动单位功能的损失，在SOD1转基因小鼠模型的MND是否发生作为一个结果，运动终端功能障碍。

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.