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Cholesterol‐containing lipid nanodiscs promote an α‐synuclein binding mode that accelerates oligomerization
The FEBS Journal ( IF 5.4 ) Pub Date : 2020-09-05 , DOI: 10.1111/febs.15551
Martin Jakubec 1, 2 , Espen Bariås 1, 2 , Samuel Furse 2 , Morten L Govasli 1, 2, 3 , Vinnit George 4 , Diana Turcu 1, 2 , Igor A Iashchishyn 5 , Ludmilla A Morozova-Roche 5 , Øyvind Halskau 1, 2
Affiliation  

Dysregulation of the biosynthesis of cholesterol and other lipids has been implicated in many neurological diseases, including Parkinson's disease. Misfolding of α‐synuclein (α‐Syn), the main actor in Parkinson's disease, is associated with changes in a lipid environment. However, the exact molecular mechanisms underlying cholesterol effect on α‐Syn binding to lipids as well as α‐Syn oligomerization and fibrillation remain elusive, as does the relative importance of cholesterol compared to other factors. We probed the interactions and fibrillation behaviour of α‐Syn using styrene–maleic acid nanodiscs, containing zwitterionic and anionic lipid model systems with and without cholesterol. Surface plasmon resonance and thioflavin T fluorescence assays were employed to monitor α‐Syn binding, as well as fibrillation in the absence and presence of membrane models. 1H‐15N‐correlated NMR was used to monitor the fold of α‐Syn in response to nanodisc binding, determining individual residue apparent affinities for the nanodisc‐contained bilayers. The addition of cholesterol inhibited α‐Syn interaction with lipid bilayers and, however, significantly promoted α‐Syn fibrillation, with a more than a 20‐fold reduction of lag times before fibrillation onset. When α‐Syn bilayer interactions were analysed at an individual residue level by solution‐state NMR, we observed two different effects of cholesterol. In nanodiscs made of DOPC, the addition of cholesterol modulated the NAC part of α‐Syn, leading to stronger interaction of this region with the lipid bilayer. In contrast, in the nanodiscs comprising DOPC, DOPE and DOPG, the NAC part was mostly unaffected by the presence of cholesterol, while the binding of the N and the C termini was both inhibited.

中文翻译:

含胆固醇的脂质纳米盘可促进α-突触核蛋白的结合模式,从而加速寡聚

胆固醇和其他脂质的生物合成失调已牵涉到许多神经系统疾病,包括帕金森氏病。帕金森氏病的主要参与者α-突触核蛋白(α-Syn)的错误折叠与脂质环境的变化有关。然而,胆固醇影响α-Syn与脂质结合以及α-Syn寡聚和原纤维形成的确切分子机制仍然难以捉摸,胆固醇与其他因素相比的相对重要性也是如此。我们使用含有两性离子和阴离子脂质模型系统(含和不含胆固醇)的苯乙烯-马来酸纳米圆盘,探索了α-Syn的相互作用和原纤化行为。使用表面等离振子共振和硫代黄素T荧光测定法监测α-Syn结合,1 H- 15使用N相关的NMR来监测响应于纳米光盘结合的α-Syn折叠,从而确定包含纳米光盘的双层的单个残基表观亲和力。胆固醇的添加抑制了α-Syn与脂质双层的相互作用,但是,显着促进了α-Syn的原纤维形成,使原纤维形成之前的滞后时间减少了20倍以上。当通过溶液状态NMR在单个残基水平上分析α-Syn双层相互作用时,我们观察到了两种不同的胆固醇效应。在由DOPC制成的纳米光盘中,胆固醇的添加调节了α-Syn的NAC部分,从而导致该区域与脂质双层的相互作用更强。相反,在包含DOPC,DOPE和DOPG的纳米光盘中,NAC部分大部分不受胆固醇存在的影响,
更新日期:2020-09-05
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