Dopamine promotes the neurodegenerative potential of β‐synuclein

A contribution of α‐Synuclein (α‐Syn) to etiology of Parkinson´s disease (PD) and Dementia with Lewy bodies (DLB) is currently undisputed, while the impact of the closely related β‐Synuclein (β‐Syn) on these disorders remains enigmatic. β‐Syn has long been considered to be an attenuator of the neurotoxic effects of α‐Syn, but in a rodent model of PD β‐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 β‐Syn. We show that in cultured rodent and human neurons a dopaminergic neurotransmitter phenotype substantially enhanced β‐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 β‐Syn, thereby enabling structural and functional modifications. Interaction of DCH with β‐Syn inhibits its aggregation, which might result in increased levels of neurotoxic oligomeric β‐Syn. Since protection of outer mitochondrial membrane integrity prevented the additive neurodegenerative effect of dopamine and β‐Syn, such oligomers might act at a mitochondrial level similar to what is suggested for α‐Syn. In conclusion, our results suggest that β‐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. β‐Synuclein has long been considered to be an attenuator for the neurotoxic effects of the Parkinson´s disease‐related α‐Synuclein, but recent studies have questioned this view. Here we add substantial further evidence to the hypothesis that β‐Synuclein should be considered as a culprit in synucleinopathies. In a novel neuronal cell culture model (a) we demonstrate that the neurotransmitter dopamine robustly enhances the neuropathological profile of β‐Synuclein, and that oxidized metabolites of dopamine can directly interact with β‐Synuclein and impact on its aggregation propensities (b). These data suggest that the toxic oligomers hypothesis appears to be as relevant for β‐Synu