Autophagy and Lysosomes in Pompe Disease

Abstract

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.

Deconstructing Pompe Disease by Analyzing Single Muscle Fibers: “To See a World in a Grain of Sand…”

“…Furthermore, we have shown that autophagic accumulation in muscle fibers was associated with resistance to enzyme replacement therapy. [21][22][23] We now demonstrate that the underlying skeletal muscle pathology and the extent of autophagy in Pompe patients are similar to those in mice. Autophagy appears to play a major role in the pathogenesis of the disease, a finding that has important implications for the effectiveness of enzyme replacement therapy with the recombinant human acid a-glucosidase.…”

Starch Binding Domain-containing Protein 1/Genethonin 1 Is a Novel Participant in Glycogen Metabolism

“…Glycogen is also transported to lysosomes where it is directly hydrolyzed to glucose by a lysosomal ␣-glucosidase (acid maltase) (6). Although probably not the major degradative mechanism under normal circumstances, the significance of this pathway is emphasized by the symptoms of patients with Pompe disease in which the ␣-glycosidase gene is mutated (7)(8)(9). The severity of the phenotype varies with the degree of impairment of glycosidase activity, in the worst cases leading to death within the 1st year after birth.…”

Relationship between glycogen accumulation and the laforin dual specificity phosphatase

“…This model of Pompe disease has massive overaccumulation of glycogen in the lysosomes of skeletal muscle as well as large accumulation of autophagic vesicles containing polysaccharide in some fiber types [34,35]. Our results could be rationalized if laforin did not have access to the bulk of the glycogen present in GAA −/− muscle.…”