The usual suspects, dopamine and alpha-synuclein, conspire to cause neurodegeneration

Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine-producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD-causing mutations in alpha-synuclein and the presence of aggregated alpha-synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of alpha-synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and alpha-synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified alpha-synuclein aggregation in the SN, resulting in greater abundance of alpha-synuclein oligomers and unique dopamine-induced oligomeric conformations. Furthermore, disruption of the dopamine-alpha-synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known alpha-synuclein and dopamine biology, review the evidence for alpha-synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. (c) 2019 International Parkinson and Movement Disorder Society