ABSTRACT

ATG7 drives macroautophagy, hereafter “autophagy”, by generating ATG12–ATG5 conjugates and lipidating Atg8 homologs including LC3. A pioneering body of work has defined the requirement of ATG7 for survival in mice and shown that neural-specific atg7 deletion causes neurodegeneration, but it has not been ascertained whether human life is compatible with ATG7 dysfunction. Recently, we defined the importance of ATG7 in human physiology by identifying twelve patients from five families harboring pathogenic, biallelic ATG7 variants causing a neurodevelopmental disorder. Patient fibroblasts show undetectable or severely diminished ATG7 protein levels, and biochemical assessment via autophagic flux and long-lived protein degradation assays demonstrated that attenuated autophagy underpins the pathology. Confirming the pathogenicity of patient variants, mouse cells expressing mutated ATG7 are unable to rescue LC3/Atg8 lipidation to wild-type levels. Our work defines mutated ATG7 as an important cause of human neurological disease and expands our understanding of autophagy in longevity and human health. We demonstrated that in certain circumstances, human survival with relatively mild phenotypes is possible even with undetectable levels of a nonredundant core autophagy protein.

 抽象的

ATG7 通过生成 ATG12-ATG5 缀合物和脂化 Atg8 同系物（包括 LC3）来驱动巨自噬（以下简称“自噬”）。一项开创性的工作明确了 ATG7 在小鼠中生存的必要条件，并表明神经特异性atg7缺失会导致神经变性，但尚未确定人类生命是否与 ATG7 功能障碍相容。最近，我们通过鉴定来自五个家庭的 12 名患者，确定了 ATG7 在人类生理学中的重要性，这些患者携带致病性双等位基因ATG7变异，导致神经发育障碍。患者成纤维细胞显示出不可检测或严重降低的 ATG7 蛋白水平，通过自噬流和长寿命蛋白降解测定进行的生化评估表明，自噬减弱是病理学的基础。表达突变ATG7 的小鼠细胞无法将 LC3/Atg8 脂化恢复至野生型水平，这证实了患者变异的致病性。我们的工作将突变的ATG7定义为人类神经系统疾病的重要原因，并扩展了我们对自噬在长寿和人类健康中的作用的理解。我们证明，在某些情况下，即使非冗余核心自噬蛋白水平不可检测，人类也可能以相对温和的表型生存。