Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice
Defining α-synuclein species responsible for Parkinson's disease phenotypes in mice
复制标题
DOI：
10.1074/jbc.ra119.007743
复制
发表时间：
2019-07-05
影响因子：
4.8
通讯作者：
Volpicelli-Daley, Laura A.
中科院分区：
文献类型：
--
作者：
Froula, Jessica M.;Castellana-Cruz, Marta;Volpicelli-Daley, Laura A.
帕金森病（PD）是一种神经退行性疾病，其特征在于由聚集的α-突触核蛋白（α-syn）组成的纤维状神经元包涵体。这些夹杂物与行为和病理PD表型相关。治疗干预的一个策略是防止这些夹杂物的形成以阻止疾病进展。α-突触核蛋白以多种结构形式存在，包括无序的非淀粉样蛋白寡聚体、有序的淀粉样蛋白寡聚体和原纤维。关键是要了解哪些构象有助于特定的PD表型。在这里，我们利用小鼠模型来探索与纤维状α-突触核蛋白相比，稳定的β-淀粉样蛋白片层寡聚体的病理学作用。我们的生物特征与透射电镜，原子力显微镜，CD光谱，FTIR光谱，分析ultracentrugation，和硫磺素T测定这些物种。然后，我们将这些不同的α-突触核蛋白形式注射到小鼠纹状体中，以确定它们诱导PD相关表型的能力。我们发现，β-折叠寡聚体产生一个小的，但显着的损失多巴胺神经元在黑质pars延髓（SNc）。然而，注射小的β-折叠纤维片段产生了最稳健的表型，包括纹状体多巴胺末梢减少、多巴胺神经元SNc丢失和运动行为缺陷。我们的结论是，尽管β折叠低聚物会引起一些毒性，但短纤维片段的有效作用可归因于它们招募单体α-突触核蛋白并在体内扩散的能力，从而有助于PD样表型的发展。这些结果表明，减少β-折叠纤维物质的形成和繁殖的策略可能是PD和相关疾病治疗干预的重要途径。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar neuronal inclusions composed of aggregated alpha-synuclein (alpha-syn). These inclusions are associated with behavioral and pathological PD phenotypes. One strategy for therapeutic interventions is to prevent the formation of these inclusions to halt disease progression. alpha-Synuclein exists in multiple structural forms, including disordered, nonamyloid oligomers, ordered amyloid oligomers, and fibrils. It is critical to understand which conformers contribute to specific PD phenotypes. Here, we utilized a mouse model to explore the pathological effects of stable beta-amyloid-sheet oligomers compared with those of fibrillar alpha-synuclein. We biophysically characterized these species with transmission EM, atomic-force microscopy, CD spectroscopy, FTIR spectroscopy, analytical ultracentrifugation, and thioflavin T assays. We then injected these different alpha-synuclein forms into the mouse striatum to determine their ability to induce PD-related phenotypes. We found that beta-sheet oligomers produce a small but significant loss of dopamine neurons in the substantia nigra pars compacta (SNc). Injection of small beta-sheet fibril fragments, however, produced the most robust phenotypes, including reduction of striatal dopamine terminals, SNc loss of dopamine neurons, and motor-behavior defects. We conclude that although the beta-sheet oligomers cause some toxicity, the potent effects of the short fibrillar fragments can be attributed to their ability to recruit monomeric alpha-synuclein and spread in vivo and hence contribute to the development of PD-like phenotypes. These results suggest that strategies to reduce the formation and propagation of beta-sheet fibrillar species could be an important route for therapeutic intervention in PD and related disorders.