Molecular Etiology of Spinal Muscular Atrophy

描述（由研究者提供）：脊髓性肌萎缩症（SMA）是一种毁灭性的神经肌肉疾病，由人类生存运动神经元1 （SMN1）基因突变引起。SMA患者通常在童年早期死亡。SMN蛋白水平降低导致疾病；完全丧失SMN表达会导致产前死亡。SMA表型的根本原因尚不清楚。SMN蛋白是一个大的寡聚复合物的一部分，在小核核糖核蛋白（snRNP）组装中起着至关重要的作用，这是所有真核细胞的核心过程。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病理是必不可少的。本提案的主要目的是利用果蝇和哺乳动物模型系统，获得SMN蛋白复合物在神经肌肉组织发育和功能中所起作用的详细知识。为了实现这一目标，我们确定了以下三个具体目标：(1)我们将分析单个sma引起的突变对果蝇SMN的一般功能和组织特异性功能的相对贡献。(2)我们将确定导致果蝇SMN表达减少导致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分析，将前两个Aims的研究结果带回小鼠系统。这些综合数据将阐明SMN表达减少的分子、细胞和发育生物学后果，并有助于更好地了解脊髓性肌萎缩症的病因。

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. PUBLIC HEALTH RELEVANCE: Spinal Muscular Atrophy (SMA) is a common genetic disease that strikes one in 6,000-8,000 young children; most of whom die before reaching the age of two years. The responsible gene has been identified, but the precise role of the gene product is not known. To aid in the development of an effective treatment for SMA, this proposal seeks to understand the underlying basis of the disease.