Raina Anupam, Leite Kristian, Guerin Sofia, Mahajani Sameehan U, Chakrabarti Kalyan S, Voll Diana, Becker Stefan, Griesinger Christian, Bähr Mathias, Kügler Sebastian
Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
Max-Planck-Institute for Biophysical Chemistry, Göttingen, Germany.
J Neurochem. 2021 Mar;156(5):674-691. doi: 10.1111/jnc.15134. Epub 2020 Aug 30.
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.
α-突触核蛋白（α-Syn）在帕金森病（PD）和路易体痴呆（DLB）病因学中的作用目前已无争议，而与之密切相关的β-突触核蛋白（β-Syn）对这些疾病的影响仍不清楚。长期以来，β-Syn一直被认为是α-Syn神经毒性作用的减弱剂，但在PD的啮齿动物模型中，β-Syn在黑质多巴胺能神经元中诱导了强烈的神经退行性变。鉴于多巴胺能黑质神经元在PD中对神经退行性变具有选择性易损性，我们现在研究多巴胺是否能促进β-Syn的神经退行性变潜能。我们发现，在培养的啮齿动物和人类神经元中，多巴胺能神经递质表型显著增强了β-Syn诱导的神经退行性变，无论多巴胺是在神经元内合成还是从细胞外空间摄取。核磁共振相互作用和硫黄素-T掺入研究表明，多巴胺及其氧化代谢产物3,4-二羟基苯乙醛（DOPAL）和多巴色素（DCH）直接与β-Syn相互作用，从而实现结构和功能修饰。DCH与β-Syn的相互作用抑制了其聚集，这可能导致神经毒性寡聚体β-Syn水平升高。由于保护线粒体外膜完整性可防止多巴胺和β-Syn的累加神经退行性变作用，这些寡聚体可能在线粒体水平发挥作用，类似于α-Syn的作用机制。总之，我们的结果表明，β-Syn通过与多巴胺代谢产物相互作用，可能在PD病因学中发挥重要的病理生理作用，因此至少对于那些依赖黑质多巴胺能神经元变性的PD症状，应重新将其视为与疾病相关的因素。
