Lafora disease (LD) 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). LD results from mutations in either of the genes encoding laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase, and mutations in either gene results in development of LD. LBs cause disease from acute neurotoxicity due to the sensitivity of neurons to energy perturbations. 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 overall focus of this Program Project Grant is to facilitate the Lafora Epilepsy Cure Initiative (LECI): which is an international collaboration devoted to the Diagnosis, Treatment, and Cure of LD. The goals of this project are to define the clinical biochemistry of LD mutations to provide a personalized diagnosis and establish therapeutic options. To achieve these goals, we will define the molecular basis of LD utilizing structural biochemistry, cellular biology, and mouse models and translate our insights into mutation-specific diagnoses and novel therapeutic approaches to ameliorate LD induced epilepsy and cure 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 neurotransmitter transporters affected in LD. Further, we will determine how laforin and malin affect 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 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 Center projects. Further, these results have significant broader implications since LD is one of five major progressive myoclonic epilepsies, and the connection between metabolic dysfunction and epilepsy is an emerging theme. 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.
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| Garcia-Gimeno, Maria Adelaida; Rodilla-Ramirez, Pilar Natalia; Viana, Rosa et al. (2018) A novel EPM2A mutation yields a slow progression form of Lafora disease. Epilepsy Res 145:169-177 |
| Lahuerta, Marcos; Aguado, Carmen; Sánchez-Martín, Pablo et al. (2018) Degradation of altered mitochondria by autophagy is impaired in Lafora disease. FEBS J 285:2071-2090 |
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| Ahonen, Saija; Seath, Ian; Rusbridge, Clare et al. (2018) Nationwide genetic testing towards eliminating Lafora disease from Miniature Wirehaired Dachshunds in the United Kingdom. Canine Genet Epidemiol 5:2 |
| Gentry, Matthew S; Guinovart, Joan J; Minassian, Berge A et al. (2018) Lafora disease offers a unique window into neuronal glycogen metabolism. J Biol Chem 293:7117-7125 |
| Augé, Elisabet; Pelegrí, Carme; Manich, Gemma et al. (2018) Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease. Glia 66:2094-2107 |
| Sanz, Pascual; Viana, Rosa; Garcia-Gimeno, Maria Adelaida (2018) AMPK Protein Interaction Analyses by Yeast Two-Hybrid. Methods Mol Biol 1732:143-157 |
| Rubio-Villena, Carla; Viana, Rosa; Bonet, Jose et al. (2018) Astrocytes: new players in progressive myoclonus epilepsy of Lafora type. Hum Mol Genet 27:1290-1300 |
| Brewer, M Kathryn; Gentry, Matthew S (2018) The 3rd International Lafora Epilepsy Workshop: Evidence for a cure. Epilepsy Behav 81:125-127 |
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