BACKGROUND & AIMS:
:In the last decades, a series of compounds, including quinones and polyphenols, has been described as having anti-fibrillogenic action on α-synuclein (α-syn) whose aggregation is associated to the pathogenesis of Parkinson's disease (PD). Most of these molecules act as promiscuous anti-amyloidogenic agents, interacting with the diverse amyloidogenic proteins (mostly unfolded) through non-specific hydrophobic interactions. Herein we investigated the effect of the vitamins K (phylloquinone, menaquinone and menadione), which are 1,4-naphthoquinone (1,4-NQ) derivatives, on α-syn aggregation, comparing them with other anti-fibrillogenic molecules such as quinones, polyphenols and lipophilic vitamins. Vitamins K delayed α-syn fibrillization in substoichiometric concentrations, leading to the formation of short, sheared fibrils and amorphous aggregates, which are less prone to produce leakage of synthetic vesicles. In seeding conditions, menadione and 1,4-NQ significantly inhibited fibrils elongation, which could be explained by their ability to destabilize preformed fibrils of α-syn. Bidimensional NMR experiments indicate that a specific site at the N-terminal α-syn (Gly31/Lys32) is involved in the interaction with vitamins K, which is corroborated by previous studies suggesting that Lys is a key residue in the interaction with quinones. Together, our data suggest that 1,4-NQ, recently showed up by our group as a potential scaffold for designing new monoamine oxidase inhibitors, is also capable to modulate α-syn fibrillization in vitro.
背景与目标:
: 在过去的几十年中,一系列化合物 (包括醌和多酚) 被描述为对 α-突触核蛋白 (α-syn) 具有抗原纤维生成作用,其聚集与帕金森氏病 (PD) 的发病机理有关。这些分子中的大多数充当混杂的抗淀粉样蛋白生成剂,通过非特异性疏水相互作用与多种淀粉样蛋白 (大部分未折叠) 相互作用。在本文中,我们研究了1,4-萘醌 (1,4-nq) 衍生物的维生素k (叶绿醌,甲萘醌和甲萘醌) 对 α-syn聚集的影响,并将其与其他抗原纤维生成分子进行了比较例如醌,多酚和亲脂性维生素。维生素k在亚化学计量的浓度下延迟了 α-syn的结晶化,导致形成短的剪切原纤维和无定形聚集体,不易产生合成囊泡的泄漏。在播种条件下,甲萘醌和1,4-nq显着抑制原纤维的伸长,这可以用它们破坏 α-syn的预制原纤维的能力来解释。二维NMR实验表明,N末端 α-syn (Gly31/Lys32) 的特定位点参与了与维生素k的相互作用,这已被先前的研究证实,表明Lys是与醌相互作用的关键残基。总之,我们的数据表明,我们小组最近发现的1,4-nq是设计新的单胺氧化酶抑制剂的潜在支架,它也能够在体外调节 α-合成纤维化。