Mechanisms of degeneration in the spinal cord and musculoskeletal system in SMA

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种致命的遗传性疾病。它是由运动神经元存活（SMN）基因突变引起的，是儿童死亡的第二大常见遗传原因。它的特点是进行性对称肢体和躯干麻痹和肌肉萎缩。目前，还没有针对SMA患者的治疗方法，因为除了知道它影响运动神经元（MNs）外，对SMN的功能和疾病的病理生物学知之甚少。尽管SMN蛋白在许多组织中表达，包括神经和非神经组织，但MNs似乎在SMA中受影响最大。目前尚不清楚SMN在引起SMA病理中的作用，以及SMN的缺失或突变如何导致选择性MN易感性。MNs的病理可能与亚细胞定位错误、功能缺失或功能异常有关。另外，MN损伤可能是骨骼肌或肌肉骨骼病理导致神经肌肉连接异常的继发结果。目前尚不清楚最初的损伤是在神经元还是肌肉，也不清楚其他器官系统是否受到影响。这里描述的项目的最终目标将是提出针对特定退行性途径的治疗方法。这一目标将通过两个具体目标来实现。第一个目标是分析脊髓MNs和骨骼肌中的细胞死亡蛋白，这些细胞死亡蛋白来自小鼠SMA模型和人类SMA患者，以便开发一种不同于SMA重建的辅助治疗方法。这一目的将验证细胞凋亡是SMA变性机制的假设，并确定所涉及的特定凋亡途径。一旦确定了特定途径，将在SMA小鼠中对其进行药物抑制，以确定这是否可以减缓或预防疾病进展。第二个目的是验证一个假设，即肌肉骨骼系统在SMA小鼠中不能正常发育，这种肌肉骨骼病理是一种主要的损害，与异常的SMN无法促进DNA的修复有关

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a fatal genetic disease. It is caused by mutations in the Survival of Motor Neuron (SMN) gene and is the second most common genetic cause of childhood mortality [6]. It is characterized by progressive symmetrical limb and trunk paralysis and muscular atrophy. Currently, there are no therapies for SMA patients, because little is known about the function of SMN and the pathobiology of the disease, except that it affects motor neurons (MNs). Although the SMN protein is expressed in many tissues, including nervous and non-nervous tissues, MNs appear to be most affected in SMA. It is not known what role SMN plays in causing SMA pathology and how deletion or mutation of SMN may lead to selective MN vulnerability. Pathology in MNs may be related to subcellular mislocalization, lack of function, or aberrant function. Alternatively, MN injury may b a secondary result of skeletal muscle or musculoskeletal pathology that causes neuromuscular junction abnormalities. It remains unclear whether the initiating insult is in neurons or muscle, and it is unknown whether other organ systems are affected. The ultimate goal of the project described here will be to suggest therapeutic approaches targeting specific degenerative pathways. This goal will be achieved by two specific aims. The first aim is to profile cell death proteins in spinal cord MNs and in skeletal muscle from a mouse model of SMA and from human SMA patients, in order to develop an adjuvant therapy for SMA distinct from SMN reconstitution. This aim will test the hypothesis that apoptosis is the mechanism for degeneration in SMA and define the specific apoptotic pathways involved. Once a specific pathway is identified, it will be pharmaceutically inhibited in SMA mice to determine whether this can slow or prevent disease progression. The second aim is to test the hypothesis that the musculoskeletal system fails to develop properly in SMA mice, and that this musculoskeletal pathology is a primary insult, related to the inability of abnormal SMN to facilitate repair of DNA double strand breaks by homologous recombination in proliferating myoblasts, rather than a secondary consequence of motor neuron disease. This aim will be accomplished by examining, histologically and biochemically, spinal cord MN and skeletal muscle pathology in embryonic and neonatal SMA mice and in human SMA autopsy tissues. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy (SMA) is the second most lethal recessive genetic childhood disease. There are no cures and no effective treatments for SMA, in large part because it is not understood how the loss of the SMN gene leads to SMA. We will investigate the molecular and cellular mechanisms which cause motor neuron cell death and muscle atrophy in SMA, in order to identify therapeutic targets for this and other neurodegenerative disorders.