Quantitative proteomic analysis of Survival Motor Neuron (SMN) missense mutants in Drosophila

Spinal Muscular Atrophy (SMA) is a devastating neuromuscular disease caused by hypomorphic loss of function in the Survival Motor Neuron (SMN) protein. SMA presents across broad spectrum of disease severity. Unfortunately, vertebrate models of intermediate SMA have been difficult to generate and are thus unable to address key aspects of disease etiology. To address these issues, we developed a Drosophila model system that recapitulates the full range of SMA severity, allowing studies of pre-onset biology as well as late-stage disease processes. In this study, TMT-based quantitative proteomic profiling was performed on mild and intermediate Drosophila models of SMA to elucidate proteins and pathways that contribute to the disease. Using this approach, we elaborated a role for the SMN complex in the regulation of innate immune signaling.

脊髓性肌萎缩症（Spinal Muscular Atrophy, SMA）是一类毁灭性神经肌肉疾病，其致病根源为运动神经元生存蛋白（Survival Motor Neuron, SMN）发生功能减退型失活。SMA的疾病严重程度跨度广泛，呈现连续的谱系特征。遗憾的是，中间型SMA的脊椎动物模型极难构建，这使得学界无法针对该病病因学的关键环节开展研究。为解决这一困境，我们开发了一套果蝇（Drosophila）模型系统，该模型可复现SMA的全部严重程度谱系，能够用于发病前生物学过程以及晚期疾病进程的相关研究。本研究针对轻度与中间型SMA果蝇模型开展基于串联质量标签（Tandem Mass Tag, TMT）的定量蛋白质组学分析，以期阐明参与疾病发生发展的蛋白质分子与信号通路。通过该研究策略，我们明确了SMN复合物在调控先天免疫信号通路中的关键作用。