This assumption is based on experimental evidence indicating that

This assumption is based on experimental evidence indicating that the endocytic and autophagic pathways can converge upstream from lysosomes: autophagosomes can fuse with late endosomes or even early endosomes. Thus, the therapeutic enzyme, which moves along the endocytic pathway from early to late endosomes and then to lysosomes, may be mis-targeted and end up in autophagosomes. This hypothesis has been confirmed experimentally. To address the issue of rhGAA trafficking in skeletal muscle we have used a unique experimental Inhibitors,research,lifescience,medical system – analysis of endocytosis of labeled GDC-0449 molecular weight recombinant enzyme in live cultured myofibers. We have demonstrated that the endocytosed therapeutic enzyme in the KO fibers

accumulates along the length of the fibers, primarily in Inhibitors,research,lifescience,medical the vesicular compartments of the autophagic areas. The recombinant enzyme, trapped in these areas, is mostly wasted since it is diverted from glycogen-filled lysosomes in the rest of the fiber, but is unable to resolve the autophagic buildup (11), which continues to expand as the disease progresses. Thus, autophagy sets up the conditions for the disruptive buildup and diversion

of recombinant enzyme away from lysosomes (19). The data from both mouse model and human studies Inhibitors,research,lifescience,medical led us to reconsider the view of the pathogenesis of the disease and the mechanisms of skeletal muscle damage. The current view, put forward more than 20 years ago, is that muscle damage occurs because Inhibitors,research,lifescience,medical unlike in other cells, lysosomes in muscle cells have a limited space in which to expand, resulting in mechanical pressure, and rupture (20, 21). According to this hypothesis, the disease progresses through multiple stages: glycogen begins to accumulate in lysosomes, which gradually increase in size and number leading to rupture of the lysosomal membrane, and allowing spilled glycogen to float into the cytoplasm. Later stages are characterized by complete replacement of contractile elements by spilled cytoplasmic glycogen. This hypothesis does not take Inhibitors,research,lifescience,medical into consideration abnormalities in multiple other vesicles of the lysosomal-degradative system, and

specifically, those involved in autophagy. 3-mercaptopyruvate sulfurtransferase We are not arguing with the idea of vesicular rupture, and in fact, at later stages we do see the disintegration of the vesicular membranes. However, the stages leading to this final point are at odds with our experimental evidence, both in an animal model and in humans; the data strongly indicate that it is not the global expansion of the lysosomes which cause skeletal muscle damage, but rather some yet unknown abnormalities in a subset of lysosomes which do not allow them to recycle autophagosomes and their content.
Glycogen Storage Disease Type II (GSDII; Pompe disease, acid maltase deficiency, MIM# 232300) is an autosomal recessive inherited disorder due to the deficiency of acid α-glucosidase (GAA; E.C.3.2.1.

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