Oligomeric species populated during α-synuclein aggregation are considered key drivers of neurodegeneration in Parkinson’s disease. However, the development of oligomer-targeting therapeutics is constrained by our limited knowledge of their structure and the molecular determinants driving their conversion to fibrils. Phenol-soluble modulin α3 (PSMα3) is a nanomolar peptide binder of α-synuclein oligomers that inhibits aggregation by blocking oligomer-to-fibril conversion. Here, we investigate the binding of PSMα3 to α-synuclein oligomers to discover the mechanistic basis of this protective activity. We find that PSMα3 selectively targets an α-synuclein N-terminal motif (residues 36–61) that populates a distinct conformation in the mono- and oligomeric states. This α-synuclein region plays a pivotal role in oligomer-to-fibril conversion as its absence renders the central NAC domain insufficient to prompt this structural transition. The hereditary mutation G51D, associated with early onset Parkinson’s disease, causes a conformational fluctuation in this region, leading to delayed oligomer-to-fibril conversion and an accumulation of oligomers that are resistant to remodeling by molecular chaperones. Overall, our findings unveil a new targetable region in α-synuclein oligomers, advance our comprehension of oligomer-to-amyloid fibril conversion, and reveal a new facet of α-synuclein pathogenic mutations.

中文翻译：

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可靶向的 N 端基序协调 α-突触核蛋白寡聚物到原纤维的转换

α-突触核蛋白聚集过程中形成的寡聚体被认为是帕金森病神经变性的关键驱动因素。然而，寡聚物靶向疗法的发展受到我们对其结构和驱动其转化为原纤维的分子决定因素的有限了解的限制。酚溶性调节蛋白 α3 (PSMα3) 是 α-突触核蛋白寡聚物的纳摩尔肽结合剂，可通过阻断寡聚物向原纤维的转化来抑制聚集。在这里，我们研究了 PSMα3 与 α-突触核蛋白寡聚体的结合，以发现这种保护活性的机制基础。我们发现 PSMα3 选择性地靶向 α-突触核蛋白 N 末端基序（残基 36-61），该基序在单聚和寡聚状态下填充不同的构象。该 α-突触核蛋白区域在寡聚物到原纤维的转化中起着关键作用，因为它的缺失使得中央 NAC 结构域不足以促进这种结构转变。与早发性帕金森病相关的遗传性突变 G51D 会导致该区域的构象波动，从而导致寡聚物到原纤维的转化延迟以及寡聚物的积累，从而抵抗分子伴侣的重塑。总的来说，我们的研究结果揭示了 α-突触核蛋白寡聚物中的一个新的靶向区域，促进了我们对寡聚物到淀粉样原纤维转化的理解，并揭示了 α-突触核蛋白致病性突变的新方面。