THE CONNECTION BETWEEN LAFORA DISEASE AND OTHER POLYGLUCOSAN BODY DISEASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lafora disease (LD) is caused by mutations in the carbohydrate phosphatase laforin. A hallmark of LD is the accumulation of insoluble carbohyrate, called Lafora bodies (LBs), in the cytoplasm of cells. While LBs accumulate in most cells, apoptosis only occurs in neurons and this eventually leads to epilepsy and death of the patient. Wolff-Parkinson-White (WPW) syndrome is a cardiac hypertrophy caused by insoluble carbohydrate accumulations resulting from mutations in the cellular energy sensor and regulator AMP-activated protein kinase (AMPK). McArdle's disease (GSD V) is a glycogen storage disease that results in increased glycogen storage in muscle caused by mutations in the PYGM gene that encodes muscle glycogen phosphorylase. Andersen's disease (GSD IV) is caused by mutations in glycogen branching enzyme and results in aberrant glycogen storage especially in the liver and heart. This proposal will define the events and determine the connection between LD and other diseases involving polyglucosan accumulations. Specific Aim 1 will identify modification of LD proteins and interacting proteins. In specific Aim 2, we will determine if post-translation modification affects laforin binding to known substrates, the localization of laforin, and/or the phosphatase of laforin. In specific aim 3, we will determine the mechanism of carbohydrate stimulated AMPK kinase activity. In doing so, we will define the fold increase in AMPK-kinase activity, the carbohydrate(s) catalyst, and the substrates affected. Finally, we will translate these findings into a mouse model of LD. The studies proposed will define connections between Lafora disease and other polyglucosan body disorders. In addition, they will better characterize carbohydrate metabolism, which is at the heart of multiple metabolic disorders including diabetes, and yield insights into novel treatments.