Megalencephalic leukoencephalopathy with subcortical cysts: study of MLC molecular pathogenesis and identification of potential therapeutic targets using astrocytes derived from patient inducible pluripotent stem cells.

This study aims at understanding the molecular defects underlying megalencephalic leukoencephalopathy with subcortical cysts (MLC) disease, a rare and still incurable genetic leukodystrophy. MLC is characterized by a slowly progressive course that leads to motor and cognitive deficits and epilepsy. Clinical conditions often worsen after trauma or common infections and patient management requires intensive parental, scholastic and social support. The majority of persons with MLC carry mutations in the MLC1 gene encoding the MLC1 protein that is highly expressed in a population of brain cells named astrocytes, but whose function is still poorly understood. Studies from our and other groups suggest that MLC1 is involved in the regulation of ion fluxes and in the response of astrocytes to inflammation and osmotic stress. Moving from this knowledge we propose to investigate how MLC1 mutations modify specific astrocyte functions that cause brain damage. This will be done through the establishment of an innovative disease model based on patient-derived cells and a combination of molecular, electrophysiological and video imaging technologies. We shall exploit the resulting knowledge to identify molecules and pathways that can be targeted pharmacologically in the attempt to restore astrocyte function(s) and potentially correct neurological deficits in MLC. We foresee that the results of this project will pave the way for the development of therapies to cure or ameliorate the quality of life of persons with MLC.