Characterisation of a conditional mouse-model of Parkinson's disease

alpha-Synuclein has been implicated in the pathophysiology of many neurodegenerative disorders, including Parkinson's disease (PD). In order to elucidate the role of this protein in the pathogenesis of PD, transgenic mice were created by using the tet-regulatable system driving the expression of human wildtype and mutated [A30P] alpha-synuclein in CNS neurons. Our studies demonstrate that the expression pattern depends on both the neuron-specific promoter and the integration site of the transgene constructs. Mice expressing high levels of human wildtype alpha-synuclein developed neuropathology and progressive motor impairment which could be stopped after blockade of expression in symptomatic mice. Mice expressing the mutated [A30P] alpha-synuclein restricted to the olfactory bulb showed significantly lower levels of dopamine and metabolites in this brain region. Thus our conditional mouse-model may help to define the role of human alpha-synuclein in synucleinopathies and might be used to demonstrate at which stage neuropathological symptoms of these diseases are reversible.