The contribution of alpha synuclein to neuronal survival and function - Implications for Parkinson's disease.
The contribution of alpha synuclein to neuronal survival and function - Implications for Parkinson's disease.
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α-突触核蛋白对神经元存活和功能的贡献--对帕金森病的意义
DOI：
10.1111/jnc.13570
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发表时间：
2016-05
影响因子：
4.7
通讯作者：
Manfredsson FP
中科院分区：
文献类型：
--
作者：
Benskey MJ;Perez RG;Manfredsson FP
α-突触核蛋白聚集(α-SYN)是一种神经病理特征，它定义了一系列统称为突触核病的疾病，其中帕金森病(PD)可以说是最具特征的。聚集的α-SYN是路易体的主要成分，而α-SYN基因的突变或倍增导致家族性PD。α-SYN负荷与帕金森病之间的高度相关性导致了α-SYN聚集通过功能获得机制产生毒性的假说。然而，α-SYN被认为在一系列重要的细胞过程中发挥作用，例如调节神经传递和对细胞应激的反应。因此，另一个具有同等解释力的假说是，α-SYN的聚集导致毒性，因为在功能性形式α-SYN被隔离成不容溶解的蛋白质聚集体之后，必要的α-SYN功能的毒性丧失。在这篇综述中，我们将概述将α-SYN与帕金森病联系起来的文献，以及从目前基于α-SYN的帕金森病动物模型获得的知识。然后，我们将从α-SYN功能丧失假说的观点来解释这些数据，并提供一个潜在的机制模型，通过该模型，α-SYN功能的丧失可能导致至少部分在帕金森病中观察到的神经变性。通过为帕金森病和共核病的发病机制提供另一种视角，这可能揭示另一种研究途径，以便为疾病改进策略确定潜在的新治疗靶点。α-突触核蛋白负荷与帕金森氏病病理之间的相关性导致了一种假说，即α-突触核蛋白聚集通过功能获得机制产生毒性。然而，在这篇综述中，我们讨论了支持另一种假设的数据，即α-突触核蛋白的聚集导致毒性，因为在功能形式的α-突触核蛋白被隔离成聚集体后，突触前末端失去了必要的α-突触核蛋白功能。
The aggregation of alpha synuclein (α‐syn) is a neuropathological feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated α‐syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the α‐syn gene result in familial PD. The high correlation between α‐syn burden and PD has led to the hypothesis that α‐syn aggregation produces toxicity through a gain‐of‐function mechanism. However, α‐syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of α‐syn results in toxicity because of a toxic loss of necessary α‐syn function, following sequestration of functional forms α‐syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking α‐syn to PD and the knowledge gained from current α‐syn‐based animal models of PD. We will then interpret these data from the viewpoint of the α‐syn loss‐of‐function hypothesis and provide a potential mechanistic model by which loss of α‐syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies. The correlation between α‐synuclein burden and Parkinson's disease pathology has led to the hypothesis that α‐synuclein aggregation produces toxicity through a gain‐of‐function mechanism. However, in this review, we discuss data supporting the alternative hypothesis that the aggregation of α‐synuclein results in toxicity because of loss of necessary α‐synuclein function at the presynaptic terminal, following sequestration of functional forms of α‐synuclein into aggregates.
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影响因子：
8.6
作者：
Appel-Cresswell, Silke;Vilarino-Guell, Carles;Farrer, Matthew J.
通讯作者：
Farrer, Matthew J.
DOI：
10.1073/pnas.0407146102
发表时间：
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影响因子：
11.1
作者：
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作者：
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DOI：
10.1073/pnas.1109526109
发表时间：
2012-02-14
影响因子：
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通讯作者：
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