Generation and Characterization of a Mouse Model of Adult Polyglucosan Body Disease
Glycogen is the primary source of stored glucose and it is similar in humans and in all other living organisms, except that the peripheral glucose chains are shorter in glycogen than in starch, the source of glucose in plants. The degree of branching and the length of the glucose chains are determined by the relative activities of two key enzymes, glycogen synthase (GS) and glycogen branching enzyme (GBE). For optimal energy metabolism, glycogen has to be well branched, otherwise it cannot be degraded efficiently when energy is needed and it cannot be synthesized promptly to store glucose and to stabilize the osmotic pressure of the cell.
Loss of GBE activity can either cause a clinical picture of childhood liver failure or a neurodegenerative disease termed Polyglucosan Body disease that can occur in neonates through adulthood. There are FDA-approved reagents that enhance autophagy, and thus help ameliorate glycogen accumulation, such as lithium chloride and Rapamycin, that can be used to clear the polyglucosan which is resistant to degradation by phosphorylase. It has also been shown that nickel and cobalt ions increase the transcription of the gene encoding GBE ( GBE1 ), via hypoxic signal transduction. This treatment did not impair cell growth or cause cell death. Iron chelators may be better suited to activate hypoxic signaling, but should be studied extensively in animal models.
Therefore, we would like to produce a mouse model for the adult form of GSD IV (Aim 1), to avoid early lethality, in which to characterize the disease (Aim 2), and to slow down or reverse the course of the disease by activating cellular mechanisms like autophagy or increasing residual branching enzyme activity with transcriptional regulators and Iron chelators (Aim 3).
Relevance of the project to IDDRC mission:
Energy storage and degradation is central to the nervous system and this project is directed at understanding the pathogenesis of Polyglucosan disease, a rare neurologic form of glycogen storage disease. It will also have a treatment component that will be directly relevant to other neurodegenerative diseases.