Dopamine Promotes The Neurodegenerative Potential Of Beta-Synuclein

A contribution of alpha-Synuclein (alpha-Syn) to etiology of Parkinson ' s disease (PD) and Dementia with Lewy bodies (DLB) is currently undisputed, while the impact of the closely related beta-Synuclein (beta-Syn) on these disorders remains enigmatic. beta-Syn has long been considered to be an attenuator of the neurotoxic effects of alpha-Syn, but in a rodent model of PD beta-Syn induced robust neurodegeneration in dopaminergic neurons of the substantia nigra. Given that dopaminergic nigral neurons are selectively vulnerable to neurodegeneration in PD, we now investigated if dopamine can promote the neurodegenerative potential of beta-Syn. We show that in cultured rodent and human neurons a dopaminergic neurotransmitter phenotype substantially enhanced beta-Syn-induced neurodegeneration, irrespective if dopamine is synthesized within neurons or up-taken from extracellular space. Nuclear magnetic resonance interaction and thioflavin-T incorporation studies demonstrated that dopamine and its oxidized metabolites 3,4-dihydroxyphenylacetaldehyde (DOPAL) and dopaminochrome (DCH) directly interact with beta-Syn, thereby enabling structural and functional modifications. Interaction of DCH with beta-Syn inhibits its aggregation, which might result in increased levels of neurotoxic oligomeric beta-Syn. Since protection of outer mitochondrial membrane integrity prevented the additive neurodegenerative effect of dopamine and beta-Syn, such oligomers might act at a mitochondrial level similar to what is suggested for alpha-Syn. In conclusion, our results suggest that beta-Syn can play a significant pathophysiological role in etiology of PD through its interaction with dopamine metabolites and thus should be re-considered as a disease-relevant factor, at least for those symptoms of PD that depend on degeneration of nigral dopaminergic neurons.