Interaction of alpha-synuclein and dopamine metabolites in the pathogenesis of Parkinson's disease: a case for the selective vulnerability of the substantia nigra.

Parkinson's disease (PD) is the most common movement disorder. Major disease symptoms are due to the loss of dopaminergic (DA) neurons in substantia nigra (SN). The pathologic hallmark of PD is Lewy bodies (LBs) in the SN and the major protein in LBs is alpha-synuclein (AS). A plethora of evidence points towards the culpability of AS in the pathogenesis of PD including: (1) linkage of AS mutations to familial forms of PD, (2) triplication of the AS locus causing PD, and (3) overexpression of AS in transgenic mice and Drosophila leads to PD-like phenotypes. Studies of purified AS have revealed its ability to interact with diverse molecules including monoamines. Monoamine metabolism is associated with oxidative stress conditions that may contribute to DA-AS interactions promoting aggregation and neuronal damage. However, in order to explain the selective vulnerability of DA neurons there needs to be a link between DA metabolism and AS aggregation. Since only the DA neurons contain significant amounts of DA, this has been hypothesized to account for the selective vulnerability of SN neurons. However, DA itself may not be toxic at physiologic relevant doses, so it is probable that other DA metabolites may play a major role in AS aggregation. In this review, we discuss the role of the DA metabolite 3,4-dihydroxyphenylacetaldehyde to provide a plausible link between DA production and metabolism, AS aggregation and the pathogenesis of PD.