Generation of Transgenic Mice with Selective and Progressive Loss of Nigrostriatal Dopaminergic Neurons

Mutations in the alpha-synuclein gene are responsible for rare, dominantly inherited forms of familial Parkinson's disease, designated PARK1 and PARK4. Furthermore, alpha-synuclein is also the major component of Lewy bodies, the characteristic protein aggregates found in affected brain regions of most patients with PD. Thus, alpha-synuclein likely plays an important role in the pathogenesis of PD. Pre-clinical models of alpha-synuclein-linked PD have been generated that develop neurodegenerative disease but none of these models fully recapitulate the hallmark neuropathological and behavioral features of PD. In particular, dopamine-containing neurons of the substantia nigra, the principal neurons associated with the major motor symptoms of PD, fail to adequately degenerate in these models.

To develop a more robust model of PD, we plan to generate alpha-synuclein transgenic mice with selective and progressive loss of nigrostriatal dopaminergic neurons. We will develop conditional transgenic mice using an innovative Cre-loxP-based knock-in strategy, to allow the expression of alpha-synuclein transgenes only in dopamine-containing neurons. This will likely help us to recapitulate the cardinal neuropathology of PD and provide more robust, relevant pre-clinical models of this disease. These models will be extremely useful for testing novel therapies aimed at halting the progression of PD.