INVESTIGATING NECROPTOSIS IN AUTOSOMAL RECESSIVE JUVENILE PARKINSONISM AND POTENTIAL RESCUE BY PHARMACOLOGICAL KAR ANTAGONISM

Mutations in the gene named PARK2 cause Autosomal Recessive Juvenile Parkinsonism (ARJP), a neurodegenerative disease characterized by death of dopamine (DA) neurons in substantia nigra pars compacta (SNc), a brain region involved in movement control. Currently, no cure is available for this disease, which boosts our effort to discover the molecular mechanisms that drive DA neuron to death and develop novel therapeutic strategies. We collected preliminary evidence that a compound able to pharmacologically block the Kainate type of glutamate receptor (KAR) prevents the degeneration of DA neurons in a murine model carrying a PARK2 mutation. Moreover, we found that DA neurons in the SNc of this model show signs of necroptosis, a novel and recently described form of neuronal death. We hypothesize that drugs blocking KAR can prevent DA neuron death in ARJP by inhibiting the necroptosis pathway. To this aim, we will test whether drugs able to block KAR rescue DA neuron dysfunction and death, and inhibit necroptosis in two mouse model of ARJP. To make a step forward in the therapy of ARJP patients, we will also investigate features of necroptosis in DA neurons derived from human induced pluripotent stem cells (iPSCs) bearing PARK2 mutations. Hence, this project will provide novel information on the mechanisms of neuron death in ARJP, and might identify a targetable neurotoxic pathway and a cure to be translated in ARJP patients.