College of Life Sciences, China Agricultural University, Beijing 100083, China.
J Cell Biol. 2013 Mar 18;200(6):731-41. doi: 10.1083/jcb.201211014. Epub 2013 Mar 11.
The molecular mechanism underlying the selective vulnerability of certain neuronal populations associated with neurodegenerative diseases remains poorly understood. Basal autophagy is important for maintaining axonal homeostasis and preventing neurodegeneration. In this paper, we demonstrate that mice deficient in the metazoan-specific autophagy gene Epg5/epg-5 exhibit selective damage of cortical layer 5 pyramidal neurons and spinal cord motor neurons. Pathologically, Epg5 knockout mice suffered muscle denervation, myofiber atrophy, late-onset progressive hindquarter paralysis, and dramatically reduced survival, recapitulating key features of amyotrophic lateral sclerosis (ALS). Epg5 deficiency impaired autophagic flux by blocking the maturation of autophagosomes into degradative autolysosomes, leading to accumulation of p62 aggregates and ubiquitin-positive inclusions in neurons and glial cells. Epg5 knockdown also impaired endocytic trafficking. Our study establishes Epg5-deficient mice as a model for investigating the pathogenesis of ALS and indicates that dysfunction of the autophagic-endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.
导致与神经退行性疾病相关的某些神经元群体易损性的分子机制仍知之甚少。基础自噬对于维持轴突稳态和防止神经退行性变很重要。本文中，我们证明了后生动物特异性自噬基因 Epg5/epg-5 缺失的小鼠表现出皮质第 5 层锥体神经元和脊髓运动神经元的选择性损伤。病理性研究显示，Epg5 敲除小鼠遭受肌肉去神经支配、肌纤维萎缩、迟发性进行性后肢瘫痪以及显著的生存能力降低，重现了肌萎缩侧索硬化症（ALS）的关键特征。Epg5 缺失通过阻止自噬体成熟为降解性自溶体而阻断自噬小体的成熟，从而导致神经元和神经胶质细胞中 p62 聚集体和泛素阳性内含物的积累，从而损害了自噬小体流。Epg5 敲低也损害了内吞运输。我们的研究确立了 Epg5 缺失小鼠作为研究 ALS 发病机制的模型，并表明自噬-溶酶体系统功能障碍导致与神经退行性疾病相关的神经元的选择性损伤。
