Synucleinopathies are a class of neurodegenerative diseases, including Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and Multiple System Atrophy (MSA). The common pathological hallmark of synucleinopathies is the filamentous α-synuclein (α-Syn) aggregates along with membrane components in cytoplasmic inclusions in the brain. β-Synuclein (β-Syn), an isoform of α-Syn, inhibits α-Syn aggregation and prevents its neurotoxicity, suggesting the neuroprotective nature of β-Syn. However, this notion changed with the discovery of disease-associated β-Syn mutations, V70M and P123H, in patients with DLB. It is still unclear how these missense mutations alter the structural and amyloidogenic properties of β-Syn, leading to neurodegeneration. Here, we characterized the biophysical properties and investigated the effect of mutations on β-Syn fibrillation under different conditions. V70M and P123H show high membrane binding affinity compared to wild-type β-Syn, suggesting their potential role in membrane interactions. β-Syn and its mutants do not aggregate under normal physiological conditions; however, the proteins undergo self-polymerization in a slightly acidic microenvironment and/or in the presence of an inducer, forming long unbranched amyloid fibrils similar to α-Syn. Strikingly, V70M and P123H mutants exhibit accelerated fibrillation compared to native β-Syn under these conditions. NMR study further revealed that these point mutations induce local perturbations at the site of mutation in β-Syn. Overall, our data provide insight into the biophysical properties of disease-associated β-Syn mutations and demonstrate that these mutants make the native protein more susceptible to aggregation in an altered microenvironment.

中文翻译：

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疾病相关的 P123H 和 V70M 突变对 β-突触核蛋白纤颤的影响。

突触核蛋白病是一类神经退行性疾病，包括帕金森病 (PD)、路易体痴呆 (DLB) 和多系统萎缩 (MSA)。突触核蛋白病的常见病理特征是丝状 α-突触核蛋白 (α-Syn) 聚集体以及脑细胞质包涵体中的膜成分。β-突触核蛋白 (β-Syn) 是 α-Syn 的同工型，可抑制 α-Syn 聚集并防止其神经毒性，表明 β-Syn 具有神经保护作用。然而，随着在 DLB 患者中发现与疾病相关的 β-Syn 突变 V70M 和 P123H，这一概念发生了变化。目前尚不清楚这些错义突变如何改变 β-Syn 的结构和淀粉样蛋白生成特性，从而导致神经变性。这里，我们表征了生物物理特性并研究了突变对不同条件下β-Syn纤颤的影响。与野生型 β-Syn 相比，V70M 和 P123H 显示出更高的膜结合亲和力，表明它们在膜相互作用中的潜在作用。β-Syn 及其突变体在正常生理条件下不会聚集；然而，蛋白质在微酸性微环境中和/或在诱导剂存在下发生自聚合，形成类似于 α-Syn 的长而无分支的淀粉样蛋白原纤维。引人注目的是，在这些条件下，与天然 β-Syn 相比，V70M 和 P123H 突变体表现出加速的纤颤。NMR 研究进一步表明，这些点突变会在 β-Syn 突变位点引起局部扰动。全面的，