Raben Nina, Takikita Shoichi, Pittis Maria G, Bembi Bruno, Marie Suely K N, Roberts Ashley, Page Laura, Kishnani Priya S, Schoser Benedikt G H, Chien Yin-Hsiu, Ralston Evelyn, Nagaraju Kanneboyina, Plotz Paul H
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-1820, USA.
Autophagy. 2007 Nov-Dec;3(6):546-52. doi: 10.4161/auto.4591. Epub 2007 Jun 15.
Autophagy is a major pathway for delivery of proteins and organelles to lysosomes where they are degraded and recycled. We have previously shown excessive autophagy in a mouse model of Pompe disease (glycogen storage disease type II), a devastating myopathy caused by a deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase. The autophagic buildup constituted a major pathological component in skeletal muscle and interfered with delivery of the therapeutic enzyme. To assess the role of autophagy in the pathogenesis of the human disease, we have analyzed vesicles of the lysosomal-degradative pathway in isolated single muscle fibers from Pompe patients. Human myofibers showed abundant autophagosome formation and areas of autophagic buildup of a wide range of sizes. In patients, as in the mouse model, the enormous autophagic buildup causes greater skeletal muscle damage than the enlarged, glycogenfilled lysosomes outside the autophagic regions. Clearing or preventing autophagic buildup seems, therefore, a necessary target of Pompe disease therapy.
自噬是蛋白质和细胞器被输送到溶酶体进行降解和再循环的主要途径。我们之前在庞贝病（II型糖原贮积病）的小鼠模型中发现了过度自噬，这是一种由糖原降解溶酶体酶酸性α-葡萄糖苷酶缺乏引起的毁灭性肌病。自噬积累是骨骼肌中的主要病理成分，并干扰了治疗性酶的递送。为了评估自噬在人类疾病发病机制中的作用，我们分析了庞贝病患者分离出的单个肌纤维中溶酶体降解途径的囊泡。人类肌纤维显示出丰富的自噬体形成以及各种大小的自噬积累区域。在患者中，与小鼠模型一样，巨大的自噬积累比自噬区域外增大的、充满糖原的溶酶体导致更大的骨骼肌损伤。因此，清除或防止自噬积累似乎是庞贝病治疗的必要靶点。
