The contributing effects of muscle, nerve and the NMJ to SMA pathology

描述（由申请人提供）：近端脊髓性肌萎缩症（SMA）是一种常见的神经肌肉疾病，由运动神经元1 （SMN1）基因的存活突变和其翻译产物SMN蛋白水平不足引起。SMA是儿童死亡最常见的遗传原因。SMA小鼠和人类患者的特征包括脊髓运动神经元丧失和骨骼肌萎缩。基于这些特征，人们普遍认为运动神经元选择性地易受SMN减少的影响，肌肉萎缩是神经退行性疾病的继发后果。尽管存在这些长期存在的信念，但关于运动神经元是否确实是唯一容易受到SMN自主作用细胞水平降低的影响，仍然存在激烈的争论。或者，神经退行性变可能是由与运动神经元密切相关的其他细胞类型的主要影响引发的。如果SMN确实在运动神经元中起作用，以确保它们的健康和存活，那么尚不清楚为什么它们而不是其他细胞对这种蛋白质水平的降低如此敏感。为了更好地了解SMA的分子和细胞原因，已经产生了基因模仿人类状况的小鼠模型。在向美国国立卫生研究院申请资助的申请中，我们概述了三个相关目标中描述的实验，以确定SMA是否是一种完全由运动神经元健康决定的疾病，以及恢复正常水平的SMN蛋白到这种细胞类型是否足以完全改善疾病表型。我们打算从两方面回答这个问题。首先，我们将选择性地恢复SMA小鼠运动神经元的SMN，并询问这是否会导致完全的表型纠正。其次，我们将选择性地消耗健康小鼠运动神经元和两种相关组织（肌肉和神经胶质）中的SMN蛋白，并研究这种操作在多大程度上造成神经肌肉病理。在第二组实验中，我们将确定为什么SMN蛋白不足会导致神经肌肉系统的选择性变性。为了回答这个问题，我们将研究减少SMN对SMA小鼠神经-肌肉突触发育的影响。如果减少的SMN破坏了该突触及其组成蛋白的发育，而这些蛋白对确保适当的神经肌肉功能至关重要，这将解释人类疾病的神经肌肉病理特征。鉴于人类中SMA的高频率，缺乏有效的治疗方法以及由此给社会带来的负担，必须尽可能及时地回答本文提出的问题。公共卫生相关性：脊髓性肌萎缩症是一种毁灭性的神经退行性疾病，是婴幼儿的主要遗传杀手。SMA目前无法治疗。了解为什么SMA会导致神经肌肉衰竭和死亡，这对于设计合适的治疗方法非常重要。在这项建议中，我们将使用人类条件的小鼠模型来确定哪些细胞类型导致神经肌肉衰竭以及它们退化的原因。我们相信我们的研究结果将深刻影响SMA成功疗法的设计。

DESCRIPTION (provided by applicant): Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene and insufficient levels of its translated product, the SMN protein. SMA is the most common genetic cause of childhood mortality. Hallmarks of the disease in SMA mice and human patients include spinal motor neuron loss and skeletal muscle atrophy. Based on these characteristics it is widely believed that motor neurons are selectively vulnerable to reduced SMN and that muscle atrophy is a secondary consequence of neurodegeneration. These long-held beliefs notwithstanding, there continues to be a vigorous debate about whether motor neurons are indeed uniquely susceptible to reduced levels of SMN acting cell autonomously within them. Alternatively, neurodegeneration could be triggered by primary effects on some other cell type closely associated with motor neurons. If SMN does function within motor neurons to ensure their health and survival, it is not clear why they and not other cells are so sensitive to reduced levels of the protein. To better understand the molecular and cellular causes of SMA, mouse models that genetically mimic the human condition have been generated. In this application for funding to the NIH, we have outlined experiments described in three related aims to determine if SMA is a disease dictated exclusively by the health of the motor neurons and whether restoring normal levels of the SMN protein to this cell type is sufficient to completely ameliorate the disease phenotype. We propose to answer this question in two ways. Firstly, we will restore SMN selectively to the motor neurons of mice with SMA and ask if this results in complete phenotypic correction. Secondly, we will selectively deplete the SMN protein in the motor neurons and two associated tissues, muscle and glia, of healthy mice and ask to what extent such manipulations create neuromuscular pathology. In a second set of experiments, we will determine why insufficient SMN protein causes a selective degeneration of the neuromuscular system. To answer this question, we will look at the effects of reduced SMN on the development of the nerve-muscle synapse of SMA mice. If reduced SMN disrupts the development of this synapse and its constituent proteins which are crucial in ensuring proper nerve-muscle function, it will explain the neuromuscular pathology so characteristic of the human disease. Given the high frequency of SMA among humans, the lack of an effective treatment and the consequent burden it places on society, it is imperative that questions such as those posed here be answered in as timely a manner as possible. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy is a devastating neurodegenerative disease and the leading genetic killer of infants and toddlers. SMA is not presently treatable. Understanding why SMA results in neuromuscular failure and death is important to designing an appropriate treatment. In this proposal, we will use mouse models of the human condition to determine which cell types contribute to neuromuscular failure and why they degenerate. We believe our results will profoundly impact the design of successful therapies for SMA.