法国神经疾病研究所Franois Ichas团队报道了合成α-突触核蛋白原纤维在小鼠体内复制引起MSA样病理。这一研究成果于2025年11月5日发表在国际顶尖学术期刊《自然》上。

在这里，该团队报告了1B原纤维的高分辨率结构分析，以及从注射1B后发生GCIs （1BP）的患病小鼠中提取的原纤维。该团队在体内展示了构象模板使原纤维菌株复制，导致MSA样的内含物病理。值得注意的是，1B和1BP的结构非常相似，与MSA11患者分离的原纤维中观察到的aSyn的折叠非常相似。

此外，将含有1BP的原无主题脑匀浆再注射到新生小鼠体内，可再现由母体合成种子1B诱导的相同MSA样病理。他们的研究结果确定了1B是一种能够在体内自我复制的合成病原体，并揭示了1B和1BP的结构特征，这些特征可能是MSA病理的基础，为治疗策略提供了见解。

据介绍，多系统萎缩（MSA）是一种病因不明的快速进展性神经退行性疾病，通常影响50-60岁的个体，并在十年内导致死亡。其特征是由纤维状α-突触核蛋白（aSyn）组成的胶质细胞质内含物（GCIs），其形成与朊病毒的繁殖相似。虽然从患有MSA的个体的大脑中提取的原纤维已经得到了结构表征，但它们仅以蛋白质方式复制的能力一直受到质疑，它们在体内诱导GCIs的能力仍未得到探索。相比之下，由重组人aSyn组装而成的合成原纤维菌株1B在体外自我复制，并在小鼠中诱导GCIs，这表明与MSA直接相关，但缺乏原子尺度上的审查。

附：英文原文

Title: Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology

Author: Burger, Domenic, Kashyrina, Marianna, van den Heuvel, Lukas, de La Seiglire, Hortense, Lewis, Amanda J., De Nuccio, Francesco, Mohammed, Inayathulla, Verchre, Jrmy, Feuillie, Ccile, Berbon, Mlanie, Arotcarena, Marie-Laure, Retailleau, Aude, Bezard, Erwan, Canron, Marie-Hlne, Meissner, Wassilios G., Loquet, Antoine, Bousset, Luc, Poujol, Christel, Nilsson, K. Peter R., Laferrire, Florent, Baron, Thierry, Lofrumento, Dario Domenico, De Giorgi, Francesca, Stahlberg, Henning, Ichas, Franois

Issue&Volume: 2025-11-05

Abstract: Multiple-system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown cause, typically affecting individuals aged 50–60 years and leading to death within a decade1,2,3. It is characterized by glial cytoplasmic inclusions (GCIs) composed of fibrillar α-synuclein (aSyn)4,5,6,7,8, the formation of which shows parallels with prion propagation9,10. While fibrils extracted from brains of individuals with MSA have been structurally characterized11, their ability to replicate in a protein-only manner has been questioned12, and their ability to induce GCIs in vivo remains unexplored. By contrast, the synthetic fibril strain 1B13,14, assembled from recombinant human aSyn, self-replicates in vitro and induces GCIs in mice15—suggesting direct relevance to MSA—but lacks scrutiny at the atomic scale. Here we report high-resolution structural analyses of 1B fibrils and of fibrils extracted from diseased mice injected with 1B that developed GCIs (1BP). We show in vivo that conformational templating enables fibril strain replication, resulting in MSA-like inclusion pathology. Notably, the structures of 1B and 1BP are highly similar and mimic the fold of aSyn observed in one protofilament of fibrils isolated from patients with MSA11. Moreover, reinjection of crude mouse brain homogenates containing 1BP into new mice reproduces the same MSA-like pathology induced by the parent synthetic seed 1B. Our findings identify 1B as a synthetic pathogen capable of self-replication in vivo and reveal structural features of 1B and 1BP that may underlie MSA pathology, offering insights for therapeutic strategies.

DOI: 10.1038/s41586-025-09698-1

Source: https://www.nature.com/articles/s41586-025-09698-1