Towards a comprehensive understanding of molecular pathogenesis for amyotrophic lateral sclerosis

肌萎缩性侧索硬化症（ALS）是一种异质性致死性神经退行性疾病，其特征是脑和脊髓中运动神经元的选择性丧失。虽然多种毒性途径包括氧化应激、神经炎症、蛋白质错误折叠和积累以及细胞内运输功能失调，都与ALS的发病机制有关，但这些多种因素之间相互作用的分子基础在很大程度上是未知的。为了解决这一问题，我们利用表达sod1突变的ALS小鼠模型研究了GFAP、Nrf2、ALS2和p62/SQSTM1在ALS发病和进展中的作用及其相互关系。结果表明，ALS2或p62/SQSTM1的缺失都会加剧ALS小鼠的运动功能障碍。重要的是，ALS小鼠中ALS2和p62/SQSTM1的同时失活进一步加速了疾病表型。因此，自噬-内溶酶体系统的功能障碍可能在运动神经元变性中起关键作用。

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of fatal neurodegenerative diseases characterized by a selective loss of motor neurons in the brain and spinal cord. Although multiple toxicity pathways including oxidative stress, neural inflammation, protein misfolding and accumulation, and dysfunctional intracellular trafficking, are implicated in the pathogenesis of ALS, molecular basis of the interplay between such multiple factors are largely unknown. To address this issue, we investigate a role of GFAP, Nrf2, ALS2, and p62/SQSTM1 , and their interrelationship in the onset and progression of ALS using mutant SOD1-expressing ALS mouse models. The results indicate that loss of either ALS2 or p62/SQSTM1 exacerbates motor dysfunction in ALS mice. Importantly, a simultaneous inactivation of ALS2 and p62/SQSTM1 in ALS mice further accelerates the disease phenotypes. Thus, dysfunction in the autophagy-endolysosomal system might play a crucial role in motor neuron degeneration.