Elucidation of synaptic changes in parkinsonism using novel PARK15 mouse models

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Mutations in the human PARK15 (FBXO7) gene have been implicated in Parkinsonian pyramidal syndrome, a juvenile form of parkinsonism. While deletion of the Fbxo7 gene does not result in the degeneration of neurons in mice, it triggers early-onset motor deficits when ablated from glutamatergic neurons of the forebrain and progressive, late-onset motor defects when deleted in dopaminergic neurons. Alterations in the level of dopamine, a critical modulator of the striatal synapse and in the levels of key synaptic proteins in the striatum strongly support the notion that synaptic integrity and essential motor circuits underwent significant changes and are causative for the motor defects. Since parkinsonism is viewed as a synaptopathy in the early stages of the disease, these observations are particularly important. The goals of this research proposal are as follows:1. The loss of FBXO7 in glutamatergic neurons in mice negatively affects their neurotransmission, causing an increase in dopamine in the striatum. The phenotype of the mice is reminiscent of pyramidal signs in PARK15 patients and of levodopa-triggered dyskinesia in PD patients. At the molecular level, we found changes in endocytosis and exocytosis pathways, and in a synapse-elimination pathway in the striatum of these mice. In addition, we discovered a striking electrophysiological phenotype in the hippocampus. Hence, our preliminary data prompt a more detailed investigation of the molecular and electrophysiological changes of the networks in forebrain.2. The deletion of Fbxo7 from the dopaminergic neurons triggers a chronic dopamine deficit in the striatum in mice, which is reminiscent of the decreasing levels of dopamine in PD patients. The proper modulation of the striatal synapse is no longer effective. As a consequence, we hypothesize that as a result of the compromised dopaminergic input, the glutamatergic synapse undergoes adaptations as well. Hence, we will focus in particular on the molecular changes at the synapses at the quantitative level but we will also monitor the electrophysiological changes in the striatum of these mice.