Neuropathology of conditional models of Parkinson's disease

Alpha-synuclein has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. This disorder is based on progressive neuropathological alterations leading to motor abnormalities that are frequently predated by olfactory dysfunction and often accompanied by cognitive decline in later stages of the disease. Whether the neurodegenerative process might be halted or even reversed is presently unknown. In order to explore whether alpha-synuclein induces these alterations we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wildtype alpha-synuclein in several brain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration, leading to progressive motor decline. Turning off transgene expression in aged mice halted progression but did not reverse the symptoms. Mice expressing the mutated (A30P) alpha-synuclein limited to the olfactory bulb showed an impaired anxiety behavior based on a smell-test and reduction of monoamines in the olfactory bulb. Our data also suggest that approaches targeting alpha-synuclein induced pathological pathways might be of benefit in early disease stages.