Conditional control of human wildtype and mutated [A30P] alpha-synuclein in a mouse model of Parkinson's disease

Alpha-synuclein, a small soluble protein is expressed primarily at presynaptic terminals in the central nervous system. It has been implicated in the pathophysiology of many neurodegenerative disorders, including Parkinson's disease and dementia with Lewy-bodies, collectively referred to as synucleinopathies. As neurodegenerative disorders like Parkinson's disease are charecterized by progressive neuropathological and clinical symptoms, conditional models of these neurodegenerative diseases are powerful means to analyze the relationship between transgene expression and progression of the disease. We have created a conditional mouse model of synucleinopathies by using the tet-off gene system combined with expression of human wildtype or mutated (A30P) alpha-synuclein. We investigated the behavioral and neuropathological effects of overexpression of human alpha-synuclein under conditional control of both the PrP promotor and the CaMKIIalpha promotor. Western blot analyses revealed that double-transgenic mice express alpha-synuclein at different levels in specific brain regions. The expression-pattern and level of human alpha-synuclein in the brain of double-transgenic mice depend on both the neuron-specific promotor and the integration site of the human alpha-synuclein construct. Histological analysis of the brainsof transgenic mice showed aberrant expression of the protein in cell soma, axons and synapses, but no Lewy body-like alpha-synuclein inclusions could be identified, yet. We currently investigate, whether focal neurodegeneration, which we observed in one 9 month-old CaMKIIalpha-h[wt]alpha-synuclein double-transgenic mouse could be reproduced. Double-transgenic males of this line performerd significantly weaker on accelerated rotarod than age-matched control animals. HPLC-analyses of double-transgenic mice that showed expression of the transgene limited to the olfactory bulb, demonstrate significantly lower levels of Dopamin, DOPAC and HVA in this brain region. In all lines administration of doxycycline downregulates alpha-synuclein expression to basal level. Our conditional mouse-model may help to define the role of human alpha-synuclein in synucleinopathies and might be used to demonstrate whether neuropathological symptoms of these diseases are reversible.