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[6]。其特征是进行性对称性肢体和躯干瘫痪以及肌肉萎缩。目前，SMA患者没有治疗方法，因为除了它影响运动神经元（MN）外，对SMN的功能和疾病的病理学知之甚少。尽管SMN蛋白在许多组织中表达，包括神经和非神经组织，但MN似乎在SMA中受影响最大。目前尚不清楚SMN在导致SMA病理中起什么作用，以及SMN的缺失或突变如何导致选择性MN脆弱性。MN的病理可能与亚细胞错误定位、功能缺乏或功能异常有关。或者，MN损伤可能B骨骼肌或肌肉骨骼病理的继发结果，导致神经肌肉接头异常。目前尚不清楚是否在神经元或肌肉中启动损伤，也不知道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实现。第一个目的是分析SMA小鼠模型和人SMA患者的脊髓MN和骨骼肌中的细胞死亡蛋白，以开发不同于SMN重建的SMA辅助治疗。这一目标将测试的假设，即细胞凋亡是在SMA变性的机制，并确定具体的凋亡途径参与。一旦确定了特定的途径，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。第二个目的是检验SMA小鼠肌肉骨骼系统不能正常发育的假设，并且这种肌肉骨骼病理学是一种原发性损伤，与异常SMN不能促进DNA修复有关。 在增殖的成肌细胞中同源重组导致的双链断裂，而不是运动神经元疾病的继发性后果。这一目的将通过检查，组织学和生物化学，脊髓MN和骨骼肌病理在胚胎和新生儿SMA小鼠和人SMA尸检组织。

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.