Aix-Marseille Université, PPSN-EA4674, Faculté des Sciences, 13013 Marseille, France.
Sci Rep. 2016 Jun 29;6:28781. doi: 10.1038/srep28781.
Calcium-permeable pores formed by small oligomers of amyloid proteins are the primary pathologic species in Alzheimer's and Parkinson's diseases. However, the molecular mechanisms underlying the assembly of these toxic oligomers in the plasma membrane of brain cells remain unclear. Here we have analyzed and compared the pore-forming capability of a large panel of amyloid proteins including wild-type, variant and truncated forms, as well as synthetic peptides derived from specific domains of Aβ1-42 and α-synuclein. We show that amyloid pore formation involves two membrane lipids, ganglioside and cholesterol, that physically interact with amyloid proteins through specific structural motifs. Mutation or deletion of these motifs abolished pore formation. Moreover, α-synuclein (Parkinson) and Aβ peptide (Alzheimer) did no longer form Ca(2+)-permeable pores in presence of drugs that target either cholesterol or ganglioside or both membrane lipids. These results indicate that gangliosides and cholesterol cooperate to favor the formation of amyloid pores through a common molecular mechanism that can be jammed at two different steps, suggesting the possibility of a universal therapeutic approach for neurodegenerative diseases. Finally we present the first successful evaluation of such a new therapeutic approach (coined "membrane therapy") targeting amyloid pores formed by Aβ1-42 and α-synuclein.
由淀粉样蛋白小寡聚物形成的钙通透性孔是阿尔茨海默病和帕金森病的主要病变物质。然而，这些毒性寡聚物在脑细胞质膜中组装的分子机制仍不清楚。在这里，我们分析并比较了包括野生型、变体和截断形式在内的大量淀粉样蛋白以及源自 Aβ1-42 和 α-突触核蛋白特定结构域的合成肽的孔形成能力。我们表明，淀粉样蛋白孔形成涉及两种膜脂质，神经节苷脂和胆固醇，它们通过特定的结构基序与淀粉样蛋白物理相互作用。这些基序的突变或缺失会破坏孔的形成。此外，在靶向胆固醇或神经节苷脂或两种膜脂质的药物存在下，α-突触核蛋白（帕金森病）和 Aβ 肽（阿尔茨海默病）不再形成 Ca(2+)通透性孔。这些结果表明，神经节苷脂和胆固醇通过一个共同的分子机制合作促进淀粉样蛋白孔的形成，该机制可以在两个不同的步骤被阻断，这表明针对神经退行性疾病的通用治疗方法的可能性。最后，我们提出了针对 Aβ1-42 和 α-突触核蛋白形成的淀粉样蛋白孔的这种新的治疗方法（称为“膜治疗”）的首次成功评估。
