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首页> 外文期刊>Amyloid: the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis >UV-induced selective oxidation of Met5 to Met-sulfoxide leads to the formation of neurotoxic fibril-incompetent α-synuclein oligomers
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UV-induced selective oxidation of Met5 to Met-sulfoxide leads to the formation of neurotoxic fibril-incompetent α-synuclein oligomers

机译：紫外线诱导的Met5选择性氧化为Met亚砜导致形成神经毒性的原纤维不相容的α-突触核蛋白低聚物

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摘要

Oxidative stress and the formation of cytotoxic aggregates of the presynaptic protein α-synuclein (AS) are two important events associated with the pathogenesis of Parkinson's disease (PD) and several other neurodegenerative diseases. In this context, extensive efforts have been made to elucidate the molecular basis of the cytotoxic synergy between oxidative stress and AS aggregation. In this study, we demonstrate that the exposure of AS to oxidative stress induced by UV radiation (ASUV) blocks the protein fibrillation, leading to the formation of highly toxic fibril-incompetent oligomers. In addition, ASUV exhibited stronger anti-fibrillogenic properties than H2O2-treated AS, inhibiting the fibrillation of unmodified AS at notably low concentrations. Mass spectrometry indicated that Met5 oxidation to Met-sulfoxide was the only modification promoted by UV exposure, which is reinforced by NMR data indicating that Met5 is the only residue whose amide resonance completely disappeared from the 1H-15N HSQC spectrum after UV exposure. This result is supported by previous data that indicate that C-terminal Met residues (Met116 and Met127) and N-terminal Met1 are less susceptible to oxidation than Met5 because of the residual structure of the disordered AS monomer. Overall, our findings suggest that specific oxidation of Met5 might be sufficient to promote the formation of highly neurotoxic oligomers of AS.
机译：氧化应激和突触前蛋白α-突触核蛋白（AS）的细胞毒性聚集体的形成是与帕金森氏病（PD）和其他几种神经退行性疾病的发病机理相关的两个重要事件。在这种情况下，已经做出了广泛的努力来阐明氧化应激和AS聚集之间的细胞毒性协同作用的分子基础。在这项研究中，我们证明AS暴露于紫外线辐射（ASUV）诱导的氧化应激中会阻止蛋白原纤化，从而导致形成高毒性的原纤维不相容的低聚物。此外，ASUV比H2O2处理的AS表现出更强的抗原纤维形成特性，在未改性的AS浓度低的情况下抑制了原纤维的原纤化。质谱表明，Met5氧化成Met亚砜是UV暴露促进的唯一修饰，而NMR数据表明，Met5是唯一的酰胺暴露在UV暴露后从1H-15N HSQC光谱完全消失的残基。该结果得到先前数据的支持，该数据表明C端Met残基（Met116和Met127）和N端Met1比Met5更不易氧化，因为无序AS单体的残留结构。总体而言，我们的发现表明，Met5的特异性氧化可能足以促进AS的高度神经毒性低聚物的形成。

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