Structural and mechanistic insights into amyloid-β and α-synuclein fibril formation and polyphenol inhibitor efficacy in phospholipid bilayers.
Structural and mechanistic insights into amyloid-β and α-synuclein fibril formation and polyphenol inhibitor efficacy in phospholipid bilayers.
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DOI：
10.1111/febs.16122
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Pukala TL
中科院分区：
文献类型：
--
作者：
Sanders HM;Jovcevski B;Marty MT;Pukala TL
在某些细胞条件下，功能性蛋白质发生错误折叠，导致在淀粉样蛋白原纤维形成之前转变为寡聚体。错误折叠的蛋白质与神经退行性疾病如阿尔茨海默病和帕金森病有关。虽然脂膜在错误折叠和疾病病因学中的重要性被广泛接受，但脂膜在治疗设计中的影响在很大程度上被忽视了。本研究采用生物物理方法，在单体、寡聚体和原纤维水平上提供了两种脂质膜系统（阴离子和两性离子）对抑制淀粉样蛋白-β 40和α-突触核蛋白淀粉样蛋白形成的作用机制。大的单层囊泡（LUV）被证明可以增加纤维化，并大大降低两种众所周知的多酚纤维抑制剂（-）-表没食子儿茶素没食子酸酯（EGCG）和白藜芦醇的有效性，然而，使用免疫印迹和离子迁移率质谱显示这是通过不同的机制发生的。特别是低聚物群体的差异影响LUV的存在下，白藜芦醇，延长相抑制剂，相比，EGCG，成核靶向抑制剂。离子迁移率质谱显示，EGCG与典型的非途径结构的单体蛋白质相互作用或诱导更紧凑的形式，然而，在LUV存在下结合减少，可能是由于在膜环境中的分配。脂质和抑制剂的竞争效应，沿着在LUV存在下抑制剂结合减少，提供了对脂质环境中抑制剂效力降低的机制理解。总之，这项研究强调，淀粉样蛋白抑制剂的设计可能会被误导，如果在开发过程中不考虑脂膜组成和结构的影响。
Under certain cellular conditions functional proteins undergo misfolding, leading to a transition into oligomers which precede formation of amyloid fibrils. Misfolding proteins are associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. While the importance of lipid membranes in misfolding and disease aetiology is broadly accepted, the influence of lipid membranes during therapeutic design has been largely overlooked. This study utilized a biophysical approach to provide mechanistic insights into the effects of two lipid membrane systems (anionic and zwitterionic) on the inhibition of amyloid-β 40 and α-synuclein amyloid formation at the monomer, oligomer and fibril level. Large unilamellar vesicles (LUVs) were shown to increase fibrillization and largely decrease the effectiveness of two well-known polyphenol fibril inhibitors, (−)-epigallocatechin gallate (EGCG) and resveratrol, however, use of immunoblotting and ion-mobility mass spectrometry revealed this occurs through varying mechanisms. Oligomeric populations in particular were differentially affected by LUVs in the presence of resveratrol, an elongation phase inhibitor, compared to EGCG, a nucleation targeted inhibitor. Ion-mobility mass spectrometry showed EGCG interacts with or induces more compact forms of monomeric protein typical of off-pathway structures, however binding is reduced in the presence of LUVs, likely due to partitioning in the membrane environment. Competing effects of the lipids and inhibitor, along with reduced inhibitor binding in the presence of LUVs, provides a mechanistic understanding for decreased inhibitor efficacy in a lipid environment. Together, this study highlights that amyloid inhibitor design may be misguided if effects of lipid membrane composition and architecture are not considered during development.
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影响因子：
5.6
作者：
Domanov, Yegor A.;Kinnunen, Paavo K. J.
通讯作者：
Kinnunen, Paavo K. J.
影响因子：
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作者：
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DOI：
10.1073/pnas.1421204112
发表时间：
2015-04-21
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
14
作者：
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影响因子：
5.1
作者：
Corpas, Ruben;Grinan-Ferre, Christian;Sanfeliu, Coral
通讯作者：
Sanfeliu, Coral