Dopamine promotes the neurodegenerative potential of β‐synuclein

Abstract

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.

Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers

“… 38 Some of these products can even interact with β‐synuclein and promote its aggregation. 39 Indeed, by regulating DA synthesis and storage, α‐synuclein might contribute to protect dopaminergic neurons from oxidation‐induced toxicity. The regulatory activities of α‐synuclein on synapse homeostasis might also be of great relevance in other neurotransmitter systems, which have been only partially examined, that is, other monoaminergic centers of the brain.…”

Semaglutide Protects against 6-OHDA Toxicity by Enhancing Autophagy and Inhibiting Oxidative Stress

“…Loss of dopaminergic neurons is a major pathological feature of Parkinson's disease, and therefore the experimental system that can study the characteristics of dopaminergic neurons is needed. In recent years, studies have started induced pluripotent stem cells (iPSCs) to differentiate into a dopaminergic neuron phenotype to generate human-derived dopaminergic neurons and have identified their susceptibility to toxicity [ 30 , 31 ]. Meanwhile, studies confirmed the presence of increased ROS accumulation and impaired autophagy in them [ 32 , 33 ].…”

Acrylamide: A Neurotoxin and a Hazardous Waste

“…Recent research has revealed that ACR-induced locomotor abnormalities and neurotoxicity are comparable to the effects seen in PD, as ACR can cause key parkinsonian pathology such as αsynuclein aggregation [61]. The prominent hallmark of PD is the depletion of monoamine neurotransmitters (NTs) known as dopamine (DA) and its associated loss of dopaminergic A9 neurons in the substantia nigra pars compacta and striatum [58,62,63]. Motor control, cognitive decline, muscular stiffness, body posture instability, and movement difficulties are symptoms associated with the loss of dopaminergic A9 neurons [62].…”

“…The prominent hallmark of PD is the depletion of monoamine neurotransmitters (NTs) known as dopamine (DA) and its associated loss of dopaminergic A9 neurons in the substantia nigra pars compacta and striatum [58,62,63]. Motor control, cognitive decline, muscular stiffness, body posture instability, and movement difficulties are symptoms associated with the loss of dopaminergic A9 neurons [62]. DA, a kind of catecholamine, is a NT that governs important functions like cognition, motor control, emotion, and neuroendocrine activity [1,7,63].…”