Fukuda Tokiko, Roberts Ashley, Ahearn Meghan, Zaal Kristien, Ralston Evelyn, Plotz Paul H, Raben Nina
Arthritis and Rheumatism Branch, Office of Science and Technology, NIAMS, National Institutes of Health, Bethesda, Maryland 20892-1820, USA.
Autophagy. 2006 Oct-Dec;2(4):318-20. doi: 10.4161/auto.2984. Epub 2006 Oct 5.
In Pompe disease, a deficiency of lysosomal acid alpha-glucosidase, intralysosomal glycogen accumulates in multiple tissues, with skeletal and cardiac muscle most severely affected.(1) Complete enzyme deficiency results in rapidly progressive infantile cardiomyopathy and skeletal muscle myopathy that is fatal within the first two years of life. Patients with partial enzyme deficiency suffer from skeletal muscle myopathy and experience shortened lifespan due to respiratory failure. The major advance has been the development of enzyme replacement therapy, which recently became available for Pompe patients. However, the effective clearance of skeletal muscle glycogen, as shown by both clinical and preclinical studies, has proven more difficult than anticipated.(2-4) Our recent work published in Annals of Neurology(5) was designed to cast light on the problem, and was an attempt to look beyond the lysosomes by analyzing the downstream events affected by the accumulation of undigested substrate in lysosomes. We have found that the cellular pathology in Pompe disease spreads to affect both endocytic (the route of the therapeutic enzyme) and autophagic (the route of glycogen) pathways, leading to excessive autophagic buildup in therapy-resistant skeletal muscle fibers of the knockout mice.
在庞贝病中，由于溶酶体酸性α-葡萄糖苷酶缺乏，溶酶体内的糖原在多个组织中蓄积，其中骨骼肌和心肌受影响最为严重。（1）完全酶缺乏导致快速进展的婴儿型心肌病和骨骼肌肌病，在生命的头两年内致命。部分酶缺乏的患者患有骨骼肌肌病，并因呼吸衰竭而寿命缩短。主要进展是酶替代疗法的发展，该疗法最近已应用于庞贝病患者。然而，临床和临床前研究均表明，有效清除骨骼肌糖原比预期的更困难。（2-4）我们最近发表在《神经病学年鉴》上的研究（5）旨在阐明这一问题，并试图通过分析溶酶体中未消化底物蓄积所影响的下游事件来超越溶酶体进行研究。我们发现，庞贝病中的细胞病理学扩散至影响内吞（治疗性酶的途径）和自噬（糖原的途径）途径，导致基因敲除小鼠抗治疗性骨骼肌纤维中自噬过度积累。
