Project Summary

Hereditary metabolic disorders affect 1 in 4000 people worldwide. In addition, 23.6 million people in the U.S. suffer from the metabolic disease diabetes. The treatment for these diseases range from productive, in the case of insulin, healthy eating, and exercise for type 1 diabetes, to non-existent in the case of Lafora disease (LD), a fatal, neurodegenerative epilepsy. LD is caused by mutations in the carbohydrate phosphatase laforin. A hallmark of LD is the accumulation of insoluble carbohydrate, 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). We recently identified both phenotypic and biochemical connections between LD and WPW. Since receiving COBRE funding in July 2008, we have discovered that i) carbohydrate accumulations in LD and WPW are very similar, ii) laforin contains an AMPK consensus phosphorylation site, and iii) AMPK phosphorylates laforin in vitro. This proposal will define these events, determine how AMPK regulates laforin, and test if LD mice exhibit WPW symptoms. Specific Aim 1 will define the details of AMPK-phosphorylation of laforin. We will identify the conditions that promote phosphorylation in vivo and map the in vivo phosphorylation site(s). In specific Aim 2, we will define the functional consequences of AMPK-phosphorylation on laforin. We will determine if AMPK phosphorylation affects laforin binding to substrates, the localization of laforin, and/or the phosphatase activity of laforin. In specific aim 3, we will determine if symptoms of WPW syndrome exist in the LD mouse model. WPW syndrome patients and mice have an increased heart weight/body weight ratio, increased glycogen in myocytes, thickening of ventricular myocardium, and abnormal myocyte conduction. We will define each of these parameters in the LD mouse. The studies proposed will define the connection between AMPK-WPW with laforin-LD.

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