Glycogen Storage Disease Type II (GSDII): Is Autophagy Beneficial or Detrimental? (PD6.002)

Abstract

Objective: To clarify the role of autophagy in the pathogenesis of Glycogen Storage Disease Type II (GSDII) in infantile and late-onset patients. Background Regulated degradation of proteins and organelles by autophagy-lysosome system is critical for muscle homeostasis. Excessive activation of autophagy-dependent degradation contributes to muscle atrophy and cachexia. Conversely, inhibition of autophagy causes accumulation of protein aggregates and abnormal organelle that leads to myofiber degeneration and myopathy. Moreover, defects in lysosome function result in severe muscle disorders such as Pompe (GSDII) and Danon diseases. GSDII is a lysosomal storage disorder caused by a deficiency of the glycogen-degrading lysosomal enzyme acid alpha-glucosidase (GAA) and is characterized by autophagosomes buildup. However, whether autophagy is detrimental or not for muscle function in Pompe patients is unclear. Design/Methods: By protein and gene expression analyses we studied muscle autophagy and atrophy markers in infantile and late-onset GSDII patients at different time points of disease progression and correlated impairment of autophagy with muscle wasting. We also monitored autophagy in patients who received recombinant alpha-glucosidase. Results: Our data show that infantile and late-onset patients have different levels of autophagic flux, accumulation of p62-positive protein aggregates and expression of atrophy-related genes. Although the infantile patients show impaired autophagic function, the late-onset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to GAA maturation in both healthy and diseased myotubes. Conclusions: Together, our data suggest that autophagy protects myofibers from disease progression and atrophy in late-onset patients. Supported by: Grants from AFM (14199) to A.N., from Telethon-Italy (GTB07001-DR) and Eurobiobank network (QLRT2001-027769) to C.A., from AFM (15504) and from Telethon-Italy (TCP04009) to M.S. Disclosure: Dr. Nascimbeni has nothing to disclose. Dr. Fanin has nothing to disclose. Dr. Masiero has nothing to disclose. Dr. Angelini has received personal compensation for activities with Genzyme Corporation. Dr. Sandri has nothing to disclose.