Alpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates.In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.

中文翻译：

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注射到嗅球后，α-突触核蛋白构象菌株会以不同的方式扩散、播种和靶向神经元细胞。


α-突触核蛋白内含物是突触核蛋白病的标志，被认为在患者大脑中以典型模式沿着神经元连接传播。现在有充足的证据支持α-突触核蛋白的病理形式在细胞培养模型中和体内以类似朊病毒的方式传播。然而，目前尚不清楚为什么相同的病理蛋白针对不同的细胞群，以不同的动力学传播并导致具有不同临床特征的多种疾病（突触核蛋白病）。蛋白质α-突触核蛋白的聚集产生不同的构象多态性，称为菌株。这些菌株表现出独特的生化、物理和结构特征，它们能够将其印记到新招募的α-突触核蛋白上。这导致人们认为在突触核蛋白病中观察到的临床异质性可能是由于不同的病理性α-突触核蛋白菌株所致。为了研究α-突触核蛋白菌株在体内的病理作用，我们注射了我们从头产生的五种不同的纯菌株（原纤维，丝带、原纤维-65、原纤维-91、原纤维-110）进入野生型雌性小鼠的嗅球。我们证明它们在不同程度上在大脑内的嗅觉网络中传播和传播病理学。我们展示了神经突或细胞体中应变依赖性包涵体的形成。我们检测到硫黄素 S 阳性内含物，表明存在成熟的淀粉样蛋白聚集体。总之，α-突触核蛋白菌株在不同程度上播种其细胞对应物的聚集，并在中枢神经系统内差异性地传播，产生不同的传播模式。 我们在这里提供了概念证明，即α-突触核蛋白组件采用的构象决定了它们在体内大脑中扩增和传播的能力。我们的观察结果支持这样的观点：α-突触核蛋白多晶型物可能是人脑内不同传播模式的基础。