MOTOR NEURON DISEASE-NEUROPHYSIOLOGY AND PATHOLOGY

描述(由申请人提供)：我们对运动神经元病(MND)发病机制的了解仍不完全。虽然许多研究集中于了解运动神经元在MND中死亡的原因，但很少有人关注运动终末在运动单位功能障碍发病机制中的可能作用。在遗传性犬脊髓性肌萎缩症(HSCMA)的犬模型中，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)，其机制是损害突触传递，但不涉及可检测到的运动终末或轴突的变性。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，SOD1转基因小鼠。我们的第一个目标将是确认初步数据，在SOD1转基因小鼠的脊髓中，肌肉的广泛失神经早于运动神经元细胞的死亡。在另一个目的中，我们将收集证据来支持这样的观点，即NMJ变性是一种兴奋性毒性的基础，与钙处理能力降低有关。我们已获得的初步数据表明，SOD1小鼠的NMJ变性不是简单的突触前丢失问题，而可能反映了一个可能需要肌肉纤维活动的与肌肉相互作用的过程，并在许多方面类似于出生后正常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所提出的几个假说。在另一项研究中，我们将确定已知存在并作用于运动终末(钙痛)的钙激活蛋白水解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终末功能障碍是否会导致SOD1转基因MND小鼠模型中运动单位功能的丧失。

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.