Viral overexpression of human alpha-synuclein in mouse substantia nigra dopamine neurons results in hyperdopaminergia but no neurodegeneration

Loss of select neuronal populations such as midbrain dopamine (DA) neurons is a pathological hallmark of Parkinsons disease (PD). The small neuronal protein -synuclein has been related both genetically and neuropathologically to PD, yet how it contributes to selective vulnerability remains elusive. Here, we describe the generation of a novel adeno-associated viral vector (AAV) for Cre-dependent overexpression of wild-type human -synuclein. Our strategy allows us to restrict -synuclein to select neuronal populations and hence investigate the cell-autonomous effects of elevated -synuclein in genetically-defined cell types. Since DA neurons in the substantia nigra pars compacta (SNc) are particularly vulnerable in PD, we investigated in more detail the effects of increased -synuclein in these cells. AAV-mediated overexpression of wildtype human -synuclein in SNc DA neurons increased the levels of -synuclein within these cells and augmented phosphorylation of -synuclein at serine-129, which is considered a pathological feature of PD and other synucleinopathies. However, despite abundant -synuclein overexpression and hyperphosphorylation we did not observe any DA neurodegeneration up to 90 days post virus infusion. In contrast, we noticed that overexpression of -synuclein resulted in increased locomotor activity and elevated striatal DA levels suggesting that -synuclein enhanced dopaminergic activity. We therefore conclude that cell-autonomous effects of elevated -synuclein are not sufficient to trigger acute DA neurodegeneration.