肌萎缩侧索硬化全新致病基因的发现及致病机制研究

肌萎缩侧索硬化（ALS）是一种选择性侵犯上下运动神经元的致死性神经变性病，常在青壮年起病，进展快，无药可医，多在起病后3～5年去世。因此，解析其发病机制及寻找治疗靶点一直是本病的研究热点和重点。前期我们发现一个全新的ALS致病基因W并证实该基因突变可导致细胞内蛋白异常聚集以及神经元轴突断裂、紊乱等典型的ALS病理表现，但具体机制不清。本项目将以前期的原创性发现和实验结果为基础，构建W基因突变的慢病毒感染细胞，携带W基因突变个体iPS细胞诱导分化的运动神经元和人源W基因突变体在神经元选择性过表达的转基因小鼠，研究W蛋白的结构特点和生理功能，筛选互作蛋白，探讨W基因突变导致ALS发生发展的可能病理机制包括神经元存活、内质网应激、蛋白质降解途径等环节的异常，上述研究有助于揭示ALS的发病机制，为临床上诊治ALS提供新的理论依据和实验基础。

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that features selective death of upper and lower motor neurons. ALS usually occurs during young adult with rapid progression and fatal outcome. Patients often die 3 to 5 years after onset of the disease. Clarifying its pathogenesis and searching for therapy targets are always the research focus and hotspot in this field. We previously identified a newly causative gene of ALS which we named W gene and found mutations in this gene could lead to typical ALS pathology including abnormal intracellular protein accumulation and neuronal axons fracture as well as disorder. However, the specific pathogenesis remains unknown. Based on our original discovery and results, we will generate lentivirus-infected cell models, motor neuron models differentiated from iPS cells of the W gene mutation carrier and transgenic mice with neuron-specific expression of mutant W. We will investigate the physiological function of W protein and identify its interacting proteins, and study the effects of W gene mutations on the potential ALS pathogenesis including neuronal survival, endoplasmic reticulum stress, and protein degradation pathway. Our ultimate aim is to elucidate the pathologic mechanism of W gene mutation caused ALS, providing new theoretical and practical basis for diagnosis and treatment of ALS.