Dementia Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Laboratory of Molecular Neuroscience, Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan.
Elife. 2020 Jul 22;9:e56825. doi: 10.7554/eLife.56825.
Abnormal α-synuclein aggregation has been implicated in several diseases and is known to spread in a prion-like manner. There is a relationship between protein aggregate structure (strain) and clinical phenotype in prion diseases, however, whether differences in the strains of α-synuclein aggregates account for the different pathologies remained unclear. Here, we generated two types of α-synuclein fibrils from identical monomer and investigated their seeding and propagation ability in mice and primary-cultured neurons. One α-synuclein fibril induced marked accumulation of phosphorylated α-synuclein and ubiquitinated protein aggregates, while the other did not, indicating the formation of α-synuclein two strains. Notably, the former α-synuclein strain inhibited proteasome activity and co-precipitated with 26S proteasome complex. Further examination indicated that structural differences in the C-terminal region of α-synuclein strains lead to different effects on proteasome activity. These results provide a possible molecular mechanism to account for the different pathologies induced by different α-synuclein strains.
异常的α-突触核蛋白聚集与几种疾病有关，并已知以类朊病毒的方式传播。在朊病毒疾病中，蛋白聚集结构（株）与临床表型之间存在关系，但是否α-突触核蛋白聚集的株的差异导致了不同的病理仍然不清楚。在这里，我们从相同的单体中产生了两种类型的α-突触核蛋白原纤维，并研究了它们在小鼠和原代培养神经元中的接种和传播能力。一种α-突触核蛋白原纤维诱导磷酸化α-突触核蛋白和泛素化蛋白聚集体的明显积累，而另一种则没有，表明形成了两种α-突触核蛋白株。值得注意的是，前者α-突触核蛋白株抑制蛋白酶体活性，并与 26S 蛋白酶体复合物共沉淀。进一步的检查表明，α-突触核蛋白株在 C 末端区域的结构差异导致对蛋白酶体活性的不同影响。这些结果提供了一种可能的分子机制来解释不同的α-突触核蛋白株引起的不同病理。
