An N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation
An N-terminal alpha-synuclein fragment binds lipid vesicles to modulate lipid-induced aggregation
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DOI：
10.1016/j.xcrp.2023.101563
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发表时间：
2023-09-20
影响因子：
8.9
通讯作者：
Mason，Jody M.
中科院分区：
文献类型：
--
作者：
Meade，Richard M.;Allen，Scott G.;Mason，Jody M.
α -突触核蛋白（αS）错误折叠和聚集成毒性构象与许多神经退行性疾病有关。在帕金森病（PD）中，这种情况发生在多巴胺能神经元内，导致细胞死亡和疾病症状。在αS聚集过程中，许多蛋白-蛋白相互作用（PPIs）在宽阔平坦的蛋白表面形成，限制了小分子干预的潜力。然而，多肽具有很大的治疗前景，因为它们可以选择性地参与和调节所涉及的大表面积，但如果结构合适，它们足够小，可以作为药物作用。在这里，我们探索αS的前25个残基（αS1-25）作为基于肽的αS聚集拮抗剂的模板。我们报道α s1 - 25以剂量依赖的方式抑制脂质诱导的αS聚集。α s1 - 25通过与脂质结合来阻止αS的结合，αS和肽都需要脂质来抑制。这些发现为PD的治疗或预防提供了潜在的机制途径。
Misfolding and aggregation of alpha-synuclein (αS) into toxic conformations is involved in numerous neurodegenerative diseases. In Parkinson's disease (PD), this occurs within dopaminergic neurons, causing cell death and disease symptoms. During αS aggregation, many protein-protein interactions (PPIs) form over broad and flat protein surfaces, limiting potential for small-molecule intervention. Peptides, however, harbor great therapeutic promise since they can selectively engage with and modulate the large surface areas involved yet are small enough to function as druggable agents if suitably structured. Here, we explore the first 25 residues of αS (αS1–25) as a template for peptide-based αS aggregation antagonists. We report that αS1–25inhibits lipid-induced αS aggregation in a dose-dependent manner. αS1–25functions by binding to lipids to prevent αS binding, with both αS and peptide requiring lipid for inhibition to occur. These findings present a potential mechanistic route for the treatment or prevention of PD.