Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.
Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid.
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DOI：
10.1073/pnas.2309700120
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发表时间：
2024-01-09
影响因子：
11.1
通讯作者：
Radford, Sheena E.
中科院分区：
文献类型：
--
作者：
Aubrey, Liam D.;Ninkina, Natalia;Ulamec, Sabine M.;Abramycheva, Natalia Y.;Vasili, Eftychia;Devine, Oliver M.;Wilkinson, Martin;Mackinnon, Eilish;Limorenko, Galina;Walko, Martin;Muwanga, Sarah;Amadio, Leonardo;Peters, Owen M.;Illarioshkin, Sergey N.;Outeiro, Tiago F.;Ranson, Neil A.;Brockwell, David J.;Buchman, Vladimir L.;Radford, Sheena E.
了解突触核蛋白如何在体外和细胞中形成淀粉样蛋白对了解疾病至关重要。先前的研究表明α-突触核蛋白的P1区（36-42残基）控制淀粉样蛋白的形成。我们在此报告了在两个肌萎缩性侧索硬化症患者中发现的γ-突触核蛋白（γSyn） （Met38 to Ile） P1区域的单核苷酸多态性。这两个人在同一基因（Glu110 to Val）上都有第二种多态性，这种多态性在一般人群中很常见。我们发现含有ile38的γSyn在体外快速形成淀粉样蛋白，而Met38不会聚集成淀粉样蛋白，而Val110具有保护性，可以减缓聚集。这些结果强调了P1序列在打破蛋白质淀粉样蛋白形成倾向之间的平衡方面的关键作用。α-、β-和γ-突触核蛋白是与脊椎动物神经系统生理过程有关的内在紊乱蛋白。α-突触核蛋白（αSyn）是与帕金森病和某些其他神经退行性疾病相关的淀粉样蛋白。大量研究集中在α - syn形成淀粉样蛋白结构的机制上，确定其NAC区域是淀粉样蛋白组装的必要和充分条件。最近的研究表明，7个残基序列（P1）是αSyn淀粉样蛋白形成所必需的。虽然γ-突触核蛋白（γSyn）与αSyn的序列相同55%，并且其病理沉积也与神经退行性疾病有关，但γSyn在体外对淀粉样蛋白形成具有弹性。在这里，我们报告了在两例肌萎缩性侧索硬化症（ALS）患者中发现的编码γSyn的SNCG基因中罕见的单核苷酸多态性（SNP）。该SNP导致该蛋白P1区域的Ile取代了Met38。这些个体在SNCG中也有第二个常见的非病理SNP，导致Glu110被Val取代。体外研究表明，Ile38变体加速了淀粉样蛋白纤维的组装。相反，Val110阻滞了原纤维的组装并减轻了Ile38的影响。Leu取代38对淀粉样蛋白的形成影响不大，Val延缓淀粉样蛋白的形成，Ala提高淀粉样蛋白的形成速度。Ile38 γSyn也导致细胞中含有γSyn的包涵体的形成。结果表明，单点取代可以促进γ - syn淀粉样蛋白的形成，并突出了P1区域在驱动另一个synuclein家族成员淀粉样蛋白形成中的作用。
Understanding how synuclein proteins form amyloid in vitro and in cells is crucial to understand disease. Previous studies showed that the P1 region (residues 36–42) of α-synuclein controls amyloid formation. We here report a single nucleotide polymorphism in the P1 region of γ-synuclein (γSyn) (Met38 to Ile) found in two individuals with amyotrophic lateral sclerosis. Both individuals have a second polymorphism in the same gene (Glu110 to Val) that is commonly found in the general population. We show that Ile38-containing γSyn forms amyloid rapidly in vitro, while Met38 does not aggregate into amyloid and Val110 is protective, slowing aggregation. The results highlight the critical role of the P1 sequence in tipping the balance between a protein’s propensity for amyloid formation. α-, β-, and γ-Synuclein are intrinsically disordered proteins implicated in physiological processes in the nervous system of vertebrates. α-synuclein (αSyn) is the amyloidogenic protein associated with Parkinson’s disease and certain other neurodegenerative disorders. Intensive research has focused on the mechanisms that cause αSyn to form amyloid structures, identifying its NAC region as being necessary and sufficient for amyloid assembly. Recent work has shown that a 7-residue sequence (P1) is necessary for αSyn amyloid formation. Although γ-synuclein (γSyn) is 55% identical in sequence to αSyn and its pathological deposits are also observed in association with neurodegenerative conditions, γSyn is resilient to amyloid formation in vitro. Here, we report a rare single nucleotide polymorphism (SNP) in the SNCG gene encoding γSyn, found in two patients with amyotrophic lateral sclerosis (ALS). The SNP results in the substitution of Met38 with Ile in the P1 region of the protein. These individuals also had a second, common and nonpathological, SNP in SNCG resulting in the substitution of Glu110 with Val. In vitro studies demonstrate that the Ile38 variant accelerates amyloid fibril assembly. Contrastingly, Val110 retards fibril assembly and mitigates the effect of Ile38. Substitution of residue 38 with Leu had little effect, while Val retards, and Ala increases the rate of amyloid formation. Ile38 γSyn also results in the formation of γSyn-containing inclusions in cells. The results show how a single point substitution can enhance amyloid formation of γSyn and highlight the P1 region in driving amyloid formation in another synuclein family member.
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影响因子：
8.6
作者：
Appel-Cresswell, Silke;Vilarino-Guell, Carles;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
影响因子：
8.4
作者：
Buell, Alexander K.
通讯作者：
Buell, Alexander K.
α-突触核蛋白的C末端可以预防骨料复制，但对于低聚至关重要。
影响因子：
5.9
作者：
Farzadfard A;Pedersen JN;Meisl G;Somavarapu AK;Alam P;Goksøyr L;Nielsen MA;Sander AF;Knowles TPJ;Pedersen JS;Otzen DE
通讯作者：
Otzen DE
影响因子：
2.9
作者：
Bodner, Christina R.;Maltsev, Alexander S.;Dobson, Christopher M.;Bax, Ad
通讯作者：
Bax, Ad
影响因子：
5.6
作者：
Tay WM;Huang D;Rosenberry TL;Paravastu AK
通讯作者：
Paravastu AK