α-Synuclein is a hallmark amyloidogenic protein component of the Lewy bodies (LBs) present in dopaminergic neurons affected by Parkinson's disease (PD). Despite an enormous increase in emerging knowledge, the mechanism(s) of α-synuclein neurobiology and crosstalk among pathological events that are critical for PD progression remains enigmatic, creating a roadblock for effective intervention strategies. One confounding question is about the potential link between α-synuclein toxicity and genome instability in PD. We previously reported that pro-oxidant metal ions, together with reactive oxygen species (ROS), act as a "double whammy" in dopaminergic neurons by not only inducing genome damage but also inhibiting their repair. Our recent studies identified a direct role for chromatin-bound, oxidized α-synuclein in the induction of DNA strand breaks, which raised the question of a paradoxical role for α-synuclein's DNA binding in neuroprotection versus neurotoxicity. Furthermore, recent advances in our understanding of α-synuclein mediated mitochondrial dysfunction warrants revisiting the topics of α-synuclein pathophysiology in order to devise and assess the efficacy of α-synuclein-targeted interventions. In this review article, we discuss the multi-faceted neurotoxic role of α-synuclein in the nucleus and mitochondria with a particular emphasis on the role of α-synuclein in DNA damage/repair defects. We utilized a protein-DNA binding simulation to identify potential residues in α-synuclein that could mediate its binding to DNA and may be critical for its genotoxic functions. These emerging insights and paradigms may guide new drug targets and therapeutic modalities.

中文翻译：

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帕金森病多巴胺能神经元细胞核和线粒体中α-突触核蛋白的多方面遗传毒性网络：新概念和挑战。

α-突触核蛋白是路易体 (LB) 的标志性淀粉样蛋白成分，存在于受帕金森病 (PD) 影响的多巴胺能神经元中。尽管新兴知识大幅增加，但对 PD 进展至关重要的 α-突触核蛋白神经生物学机制和病理事件之间的串扰仍然是个谜，这为有效的干预策略设置了障碍。一个令人困惑的问题是 α-突触核蛋白毒性与 PD 基因组不稳定性之间的潜在联系。我们之前报道过，促氧化金属离子与活性氧（ROS）一起，对多巴胺能神经元产生“双重打击”，不仅诱导基因组损伤，还抑制其修复。我们最近的研究确定了染色质结合的氧化 α-突触核蛋白在诱导 DNA 链断裂中的直接作用，这提出了 α-突触核蛋白的 DNA 结合在神经保护与神经毒性中的矛盾作用的问题。此外，我们对 α-突触核蛋白介导的线粒体功能障碍的理解的最新进展需要重新审视 α-突触核蛋白病理生理学的主题，以便设计和评估 α-突触核蛋白靶向干预措施的功效。在这篇综述文章中，我们讨论了 α-突触核蛋白在细胞核和线粒体中的多方面神经毒性作用，特别强调了 α-突触核蛋白在 DNA 损伤/修复缺陷中的作用。我们利用蛋白质-DNA 结合模拟来识别 α-突触核蛋白中的潜在残基，这些残基可以介导其与 DNA 的结合，并且可能对其基因毒性功能至关重要。这些新兴的见解和范例可能会指导新的药物靶点和治疗方式。