肌萎缩侧索硬化(ALS)是一种致死性的神经变性疾病，基因突变,如SOD1，TDP-43，C9orf72等是其鉴定明确的病因。这些ALS相关的突变基因编码的蛋白易于形成聚集。自噬关联的FYVE蛋白（ALFY）是选择性自噬通路中降解易聚集蛋白的关键蛋白，而且还参与自噬体形成和融合,但在ALS中的作用尚不清楚。研究中我们发现ALFY主要位于运动神经元；突变SOD1，病理性TDP-43片段等使ALFY显著减少。由于ALFY的减少导致了选择性自噬清除能力下降，进而引起一些列的细胞毒性事件。因此我们推测ALFY显著减少导致的选择性自噬障碍是引起运动神经元变性的一个重要机制。为验证这一假说，我们在细胞和动物水平，采用分子生物学，组织形态学，基因工程学等手段，证实ALFY减少导致运动神经元变性，揭示ALFY保护作用的机制，应用9型重组ALFY腺相关病毒干预ALS动物模型，探索控制疾病进展的治疗手段和靶点。

Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by motor neuron death. The mechanism is not clear, but related with the aggregation. Up to now, the identified canse for ALS is the gene mutation, such as, SOD1,TDP-43 and C9orf72. The protein tranlated by the mutant gene is prone to form aggregates. Autohpagy linked FYVE protein(ALFY) is a essencial protein involved in the selective autophagy for the aggregation degradation. ALFY not only recruited the aggregation into the autophagy, but take part in the autophagy matuer and fusion.But, it is not clear whether the ALFY play a role in the pathogenesis of ALS and has protective action in the motor neuron degeneration. In our study, we found ALS related protein, mutant SOD1,TDP-25 significantly reduced the level of ALFY, which is mainly locted in the nuclear of motor neuron.So, we hypothysized that ALFY might play an essencial role in the mechanism of motor neuron death. In order to explore this idea, we will study the function of ALFY in the motor neuron degeneration,and the mechanism of ALFY's protection. We will also establish AAV9 recommbinant with ALFY to express in the central nervous system to identify the ALFY's role in vivo.