Dopamine neuron dysfunction and loss in thePrknR275W mouse model of Juvenile Parkinsonism

Abstract

Mutations in thePRKNgene encoding the protein PARKIN cause Autosomal Recessive Juvenile Parkinsonism (ARJP). Harnessing this mutation to create an early-onset Parkinson’s disease (PD) mouse model would provide a unique opportunity to clarify the mechanisms involved in the neurodegenerative process and lay the groundwork for the development of neuroprotective strategies. We created a knock-in mouse carrying the homozygousPrknR275W mutation, which is the missense mutation with the highest allelic frequency inPRKNpatients. InPrknR275W mice, we analysed the anatomical and functional integrity of the nigrostriatal pathway, including striatal DA content and evoked striatal dopamine (DA) release, as well as the motor phenotype.We report here thatPrknR275W mice show early DA neuron dysfunction, age-dependent loss of DA neurons in the substantia nigra, decreased DA content and stimulus-evoked DA release in the striatum, and progressive motor impairment. Together, these data show that thePrknR275W mouse recapitulates key features of ARJP. Thus, these studies fill a critical need in the field by introducing a promising new PD model in which to study causative mechanisms of the disease, as well as test therapeutic strategies.