Lafora Epilepsy - Basic Mechanisms to Therapy (Project 4 Barcelona Subaward)

Lafora disease (LD), one of five major progressive myoclonic epilepsies, is a fatal, recessive neurodegenerative disorder that presents as an epileptic event in the 2nd decade of life. A hallmark of LD is the accumulation of cytoplasmic, hyperphosphorylated, water-insoluble glycogen-like particles called Lafora bodies (LBs). These inclusions occur throughout the body, but disease results from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. LD results from mutations in either of the genes encoding laforin, a glucan phosphatase, or malin, an E3 ubiquitin ligase, and mutations in either gene results in LBs. Associated with LB formation, cells display multiple markers indicating perturbations in critical cellular pathways, including increased endoplasmic reticulum stress, autophagy, ROS production, and others. The goal of this project is define the clinical biochemistry of LD mutations in the two causative proteins laforin and malin and establish therapeutic options to ameliorate LD induced epilepsy with the ultimate goal of curing LD. We will first utilize integrated structural and functional tools to define the physical and cellular perturbations caused by LD mutations in both laforin and malin. These approaches will allow us to define the basis of neuronal-specific toxicity leading to disease. We will then develop personalized approaches to diagnosis and treat LD patients. We will define the role of ion channels and neurotransmitter transporters affected in LD. Further, we will determine how laforin and malin affect channel and transporter homeostasis and how LD mouse models respond to treatment of symptoms with antiepileptic drugs. Lastly, we will establish the beneficial effect of pharmacological intervention targeting proteostasis and novel compounds that promote read-through of premature termination codons. Embedded in these approaches is the development of a novel bioassay will allow patient-specific diagnosis and definition of molecular sub-types of the disease, key to each of the LECI 2020 projects. Cumulatively, these results will allow personalized therapeutic options that are developed to promote recovery of molecular and cellular function as a means of treating and curing LD.