Misfolding of the protein α-synuclein contributes to the formation of the intracellular inclusion, Lewy bodies. Although these structures are not exclusive to Parkinson's disease, nevertheless, their presence in the substantia nigra is mandatory for the pathological diagnosis of the disorder. Therefore, there must be a focus on the pathological mechanisms responsible for Lewy body generation. Recent studies have suggested that α-synuclein has the potential to operate as the enzyme ferrireductase. Perhaps in the early diseased state, overexpression or mutation of alpha-synuclein/ferrireductase invokes the dyshomeostasis of iron (III)/(II) only, while in advanced stages, accumulation of iron in particular areas of the brain follows. Furthermore, the loss of an important iron chelator, neuromelanin (due to dopaminergic neuronal death), may then result in the release and increase in unbound free iron. Iron could generate reactive oxygen species, which could instigate a torrent of cellular deleterious processes. In addition, loss of energy supply may contribute to the alteration in activity of enzymes involved in the mitochondrial respiratory chain and would, therefore, confer a vulnerability to the dopaminergic neurons in the substantia nigra. Therefore, the ferrireductase alpha-synuclein may hold the key for major pathology of Parkinson's disease. In conclusion, we hypothesize that environmentally or genetically overexpressed and/or mutated α-synuclein/ferrireductase causes iron dyshomeostasis without increase of free iron concentration in the early phases of PD, while increased iron concentration accompanied by iron dyshomeostasis is a marker for progressed PD stages. It is essential to elucidate these degenerative mechanisms, so as to provide effective therapeutic treatment to halt or delay the progression of the illness already in the early phase of PD. The development of iron chelators seems to be a reasonable approach.

中文翻译：

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α-突触核蛋白作为亚铁还原酶在与帕金森氏病相关的神经变性中的作用。

蛋白α-突触核蛋白的错误折叠有助于形成细胞内包涵体路易体。尽管这些结构不是帕金森氏病所独有的，但是它们在黑质中的存在对于疾病的病理诊断是必不可少的。因此，必须关注引起路易体生成的病理机制。最近的研究表明，α-突触核蛋白具有作为亚铁还原酶的潜力。也许在早期疾病状态下，α-突触核蛋白/铁还原酶的过度表达或突变仅引起铁（III）/（II）的动态平衡，而在晚期阶段，随后会在大脑的特定区域累积铁。此外，重要的铁螯合剂神经黑色素的丧失（由于多巴胺能神经元死亡），然后可能导致释放并增加未结合的游离铁。铁可能产生活性氧，从而激起大量的细胞有害过程。另外，能量供应的损失可能有助于线粒体呼吸链中所涉及的酶活性的改变，因此，会给黑质中的多巴胺能神经元带来脆弱性。因此，亚铁还原酶α-突触核蛋白可能是帕金森氏病主要病理的关键。总之，我们假设环境或遗传上过表达和/或突变的α-突触核蛋白/铁还原酶引起铁稳态异常，而PD早期游离铁浓度没有增加，而铁浓度升高并伴有铁稳态异常是PD阶段进展的标志。阐明这些退行性机制至关重要，以便提供有效的治疗方法来中止或延迟PD早期的疾病发展。铁螯合剂的开发似乎是一种合理的方法。