Role of α- and β-Synucleins in the Axonal Pathology of Parkinson's Disease and Related Synucleinopathies.
Role of α- and β-Synucleins in the Axonal Pathology of Parkinson's Disease and Related Synucleinopathies.
复制标题
DOI：
10.3390/biom5021000
复制
发表时间：
2015-05-19
期刊：
影响因子：
5.5
通讯作者：
Hashimoto M
中科院分区：
文献类型：
--
作者：
Sekigawa A;Takamatsu Y;Sekiyama K;Hashimoto M
轴突硬化是中枢神经系统中各种类型的病症（包括神经退行性疾病）中轴突病的组织学标志。鉴于轴突病变在神经退行性变的早期阶段中的关键作用，轴突损伤可能是很好的模型，可以为α-突触核蛋白病（包括帕金森病和路易体痴呆（DLB））的早期发病机制提供线索。在这篇简短的综述中，基于我们最近的研究以及其他积累的研究，讨论了这种可能性。与目前认为自噬-溶酶体系统的功能障碍可能在轴突突触的形成中起主要作用的观点一致，我们的研究表明，来自表达人野生型α-突触核蛋白（α S-球）或DLB连接的P123 H β-突触核蛋白（β S-球）的转基因小鼠的球，小轴突突触，含有自噬体样膜。然而，在α S球中观察到其他病理特征，如异常线粒体、氧化应激增强和LRRK 2积累，而在β S球中未观察到。总的来说，预测αS和βS可能通过相似但不同的机制参与轴突病变，因此有助于不同的轴突病变。对轴索神经元的进一步研究可能有助于阐明早期α-突触核蛋白病的致病机制，并阐明针对这些毁灭性疾病的疾病修饰治疗策略。
Axonal swellings are histological hallmarks of axonopathies in various types of disorders in the central nervous system, including neurodegenerative diseases. Given the pivotal role of axonopathies during the early phase of neurodegenerative process, axonal swellings may be good models which may provide some clues for early pathogenesis of α-synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies (DLB). In this mini-review, such a possibility is discussed based on our recent studies as well as other accumulating studies. Consistent with the current view that dysfunction in the autophagy-lysosomal system may play a major role in the formation of axonal swellings, our studies showed globule, small axonal swellings, derived from transgenic mice expressing either human wild-type α-synuclein (αS-globule) or DLB-linked P123H β-synuclein (βS-globule), contained autophagosome-like membranes. However, other pathological features, such as abnormal mitochondria, enhanced oxidative stress and LRRK2 accumulation, were observed in the αS-globules, but not in the βS-globules. Collectively, it is predicted that αS and βS may be involved in axonopathies through similar but distinct mechanisms, and thus, contribute to diverse axonal pathologies. Further studies of the axonal swellings may lead to elucidating the pathogenic mechanism of early α-synucleinopathies and illuminating a strategy for a disease-modifying therapy against these devastating disorders.