Analysis of neuronal alterations associated to PARK2 mutations and their rescue by genetic and pharmacological therapies targeting kainate receptors

Mutations in the PARK2 gene cause hereditary juvenile Parkinson's Disease (ARJP), which is currently incurable. The PARK2 gene encodes the protein parkin. Previous studies have shown that parkin regulates synapse function and that PARK2 mutations cause neuron death by a mechanism called "excitotoxicity". Excessive stimulation of glutamate receptors causes excitotoxicity, and we recently showed that parkin regulates glutamate receptors of the kainate type (kainate receptor, KAR) by interacting with the GluK2 subunit. Our study showed that the PARK2 in vitro cell culture model displays increases in GluK2/KAR function and that GluK2 levels are increased in PARK2 patient brains. We hypothesize that the upregulation of KAR function underlies dopaminergic neuron death in the brain of patients with PARK2 mutations. This research proposal aims to study an ARJP mouse model and human dopaminergic neurons derived from the iPS cells of PARK2 patients to understand whether genetic and pharmacological therapies aimed to inhibit KAR reverts the neurodegeneration.