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.
Transgenic mice were generated as proposed, but did not show significant differences from previously generated alpha-synuclein transgenic mice. Additional characterization is ongoing.
Results of this work were published in the journal Molecular Neurodegeneration.