Department of Neurology, University Medicine Göttingen, Göttingen 37073, Germany.
Department of Neurology, University Medicine Göttingen, Göttingen 37075, Germany.
Hum Mol Genet. 2021 Apr 26;30(3-4):247-264. doi: 10.1093/hmg/ddab036.
Beta (ß)-synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson's disease-related alpha (α)-synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in central nervous system (CNS) neurons in vitro and in vivo, albeit at a slower pace as compared with α-Syn. Here, we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of dementia with Lewy bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but it has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but it does not aggravate neurodegeneration. ß-Syn wild type (WT), V70M and P123H formed proteinase K-resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared with α-Syn. Under cell-free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared with WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, which are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn and is thus likely to be directly involved into the etiology of DLB. Overall, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.
β-突触核蛋白（β-Syn）长期以来被认为是帕金森病相关的α-突触核蛋白（α-Syn）蛋白引起的神经病理学效应的抑制剂。然而，最近的研究表明，过量的β-Syn 可以在体外和体内形成聚集体并诱导中枢神经系统（CNS）神经元的神经退行性变，尽管与α-Syn 相比速度较慢。在这里，我们证明在散发性路易体痴呆（DLB）病例中检测到的β-Syn 突变 V70M 和在家族性 DLB 病例中检测到的 P123H 可显著加重β-Syn 的神经毒性作用。有趣的是，这两种突变触发了相互排斥的途径。β-Syn V70M 增强了形态线粒体恶化和多巴胺能和非多巴胺能神经元的变性，但对神经元网络活动没有影响。相反，β-Syn P123H 沉默了神经元网络活动，但没有加重神经退行性变。β-Syn 野生型（WT）、V70M 和 P123H 在神经元内形成了蛋白酶 K 抗性的细胞内原纤维，尽管与α-Syn 相比，它们的 C 末端不太稳定。在无细胞条件下，β-Syn V70M 的原纤维形成速度比 WT β-Syn 慢得多，而 P123H 原纤维则呈现出独特的表型，其特征是大量短而截断的原纤维。因此，V70M 和 P123H 可能导致β-Syn 的结构改变，这与它们独特的神经病理学特征有关。这些神经病理学特征引起的病变程度与过量的α-Syn 几乎相同，因此可能直接涉及 DLB 的病因。总的来说，这项研究为β-Syn 突变引起的不同疾病机制提供了深入的了解。
