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

Abstract

Loss of select neuronal populations such as midbrain dopamine (DA) neurons is a pathological hallmark of Parkinson disease (PD). The small neuronal protein alpha-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 alpha-synuclein. Our strategy allows us to restrict alpha-synuclein to select neuronal populations and hence investigate the cell-autonomous effects of elevated alpha-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 alpha-synuclein in these cells. AAV-mediated overexpression of wildtype human alpha-synuclein in SNc DA neurons increased the levels of alpha-synuclein within these cells and augmented phosphorylation of alpha-synuclein at serine-129, which is considered a pathological feature of PD and other synucleinopathies. However, despite abundant alpha-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 alpha-synuclein resulted in increased locomotor activity and elevated striatal DA levels suggesting that alpha-synuclein enhanced dopaminergic activity. We therefore conclude that cell-autonomous effects of elevated alpha-synuclein are not sufficient to trigger acute DA neurodegeneration.