Molecular Etiology of Spinal Muscular Atrophy

描述(由研究人员提供)：脊髓性肌萎缩症(SMA)是一种毁灭性的神经肌肉疾病，由人类存活运动神经元1(SMN1)基因突变引起。SMA患者通常在儿童时期过早死亡。SMN蛋白水平降低会导致这种疾病；SMN表达的完全丧失会导致产前死亡。SMA表型的潜在原因尚不清楚。SMN蛋白是一个大的低聚复合体的一部分，它在小核核糖核蛋白(SnRNP)组装中起着至关重要的作用，这是一个对所有真核细胞都至关重要的过程。也有证据表明，SMN在神经元和肌肉中执行额外的组织特异性功能。然而，SMN的这些组织特异性功能的分子细节尚不清楚。因此，更多地了解SMN在神经肌肉发育和功能中的作用，对于我们理解SMA的病理学是至关重要的。这项建议的主要目的是利用果蝇和哺乳动物模型系统，详细了解SMN蛋白复合体在神经肌肉系统的发育和功能中所起的作用。为了解决这一目标，我们定义了以下三个具体目标：(1)我们将分析单个SMA导致的突变对果蝇SMN的一般功能和组织特异性功能的相对贡献。(2)我们将确定果蝇SMN表达减少导致所观察到的肌肉缺陷的细胞和分子机制。(3)我们将通过使用特定的转基因和分子检测，将前两个目标的结果带回小鼠系统。结合这些数据将阐明SMN表达减少的分子、细胞和发育生物学后果，并有助于更好地理解脊髓肌萎缩的病因。

DESCRIPTION (provided by investigator): Spinal Muscular Atrophy (SMA) is a devastating neuromuscular disorder, caused by mutation of the human survival motor neuron 1 (SMN1) gene. Patients with SMA typically die early in childhood. Reduced levels of SMN protein cause the disease; complete loss of SMN expression results in prenatal lethality. The underlying cause of the SMA phenotype is not yet known. SMN protein is part of a large, oligomeric complex that plays an essential role in small nuclear ribonucleoprotein (snRNP) assembly, a process central to all eukaryotic cells. There is also evidence that SMN carries out additional tissue-specific functions in neurons and muscles. However, the molecular details of these tissue-specific functions of SMN are unclear. Thus learning more about SMN's role in neuromuscular development and function is essential for our understanding of SMA pathology. The major objective of this proposal is to obtain detailed knowledge of the role played by the SMN protein complex in the development and function of the neuromusculature, using Drosophila and mammalian model systems. To address this objective we have defined the following three Specific Aims: (1) We will assay the relative contributions of individual SMA-causing mutations on the general versus the tissue-specific functions of SMN in Drosophila. (2) We will identify the cellular and molecular mechanisms that lead to the observed muscle defects caused by reduced Drosophila SMN expression. (3) We will bring the findings from the first two Aims back into the mouse system through the use of specific transgenes and molecular assays. The combined data will elucidate the molecular, cellular and developmental biological consequences of reduced SMN expression and lead to a better understanding of the etiology of Spinal Muscular Atrophy.