Recent research in the laboratory has led us to study the lysosomal disposal of glycogen. Our work has suggested that the glycogen-binding protein Stbd1 may participate in mediating an autophagy- like mechanism for the transfer of glycogen to lysosomes and furthermore may allow for the preferential trafficking, hence removal, of glycogen that accumulates abnormal structure, as characterized by increased covalent phosphorylation and decreased branching. Certain cardiac glycogenoses, as observed in Pompe disease, Danon disease, and Wolff-Parkinson-White syndrome, have in common the hyper-accumulation of glycogen in vesicular compartments within cardiomyocytes.. The current proposal is aimed at understanding how Stbd1 is involved in this process.
Aim (i) will utilize cell-based experiments to examine the mechanism of glycogen trafficking and to test whether manipulations of cells to disturb glycogen structure influences glycogen trafficking. The goal of Aim (ii) is to test whether genetic manipulation of vesicular glycogen trafficking can affect the phenotypes of two established mouse models of cardiac glycogenoses. The first, the Gaa-/- mouse, duplicates most features of Pompe disease. In the second, transgenic over- expression in heart of mutant Prkag2, provides a rodent version of Wolff-Parkinson-White syndrome. Both mouse lines are associated with massive cardiac overaccumulation of glycogen, in lysosomes or late endosomic vesicles, which is believed to be important to the pathology of the corresponding human disease. We are working on two other genetic mouse models that could impact intracellular glycogen trafficking. The first is a conditional knockout of the Stbd1 gene;based on our proposal for the function of Stbd1, we would anticipate that the absence of Stbd1 would severely limit the transport of glycogen to the lysosome. The second mouse line is malin-/- mice, generated primarily as a model of another disorder, Lafora disease. The function of malin in vivo is still under active investigation but one hypothesis for its function is that it promotes lysosomal disposal of abnormally structured glycogen. Thus, both of these mouse models could suppress vesicular glycogen trafficking. By crossing these mice with either Gaa-/- or Prkag2 mutant mice, we hypothesize that limitation of glycogen trafficking to the lysosome may alleviate symptoms of Pompe or WPW. Instead, one would expect a build-up of cytosolic glycogen, more similar to what is found in McArdle disease, which has a much less severe phenotype. In crude terms, we would hope to convert one glycogenosis to a less serious one. The most important outcome though would be to indicate whether therapies that specifically target glycogen trafficking might be a fruitful approach for the treatment of Pompe disease or Wolff-Parkinson-White syndrome.
Glycogen is a storage form of sugar that normally accumulates in cells. However, in certain disease states abnormal glycogen accumulates and impairs cell function. This proposal examines whether manipulation of a particular mechanism for glycogen disposal (the lysosomal pathway) can alleviate the damage caused by abnormal glycogen in certain heart diseases.
|Roach, Peter J (2015) Glycogen phosphorylation and Lafora disease. Mol Aspects Med 46:78-84|
|Roach, Peter J; Depaoli-Roach, Anna A; Hurley, Thomas D et al. (2012) Glycogen and its metabolism: some new developments and old themes. Biochem J 441:763-87|
|Roach, Peter J (2011) Are there errors in glycogen biosynthesis and is laforin a repair enzyme? FEBS Lett 585:3216-8|