Heras-Garvin Antonio, Stefanova Nadia
Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Front Synaptic Neurosci. 2020 Sep 21;12:584536. doi: 10.3389/fnsyn.2020.584536. eCollection 2020.
Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson's disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of α-syn constitutes one of the pathological hallmarks of these disorders, also referred to as α-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether α-syn aggregation is cause or consequence of the pathogenic events underlying α-synucleinopathies remains unclear and under discussion. Recently, different and studies have shown the ability of pathogenic α-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous α-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that α-syn should be considered a prion protein. Here we present an update of what we know about α-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of α-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.
自30年前被发现以来，α-突触核蛋白（α-syn）一直是神经科学领域研究最多的蛋白质之一。全球数十个研究团队不仅试图揭示其在中枢神经系统（CNS）中的作用，还试图揭示其在其他器官中的作用。α-syn与脑内稳态的几个重要过程有关，如神经递质释放、突触功能和可塑性。然而，尽管在这方面付出了努力，α-syn的主要功能仍然未知。此外，当发现其基因突变与帕金森病（PD）相关时，α-syn成为神经科医生和神经科学家关注的蛋白质，而当在PD、路易体痴呆（DLB）和多系统萎缩（MSA）患者的大脑中观察到α-syn蛋白沉积时，更是如此。目前，α-syn的异常聚集是这些疾病的病理特征之一，这些疾病也被称为α-突触核蛋白病，并且它被用于死后诊断标准。α-syn聚集是α-突触核蛋白病潜在致病事件的原因还是结果仍不清楚，仍在讨论中。最近，不同的研究表明，致病性α-syn不仅能够在中枢神经系统内的细胞之间传播，还能从肠道、唾液腺等外周部位通过嗅觉网络进入中枢神经系统，诱导内源性α-syn异常错误折叠，并导致动物模型中的神经退行性变以及运动和认知障碍。因此，有人提出α-syn应被视为一种朊病毒蛋白。在此，我们介绍关于α-syn功能、聚集和传播及其在神经退行性变中的作用的最新知识。我们还讨论了支持α-syn假设的朊病毒性质的基本原理和研究结果、其不足之处以及疾病修饰疗法研究和开发的未来前景。
