α-突触核蛋白和 GBA1 在帕金森病中的分子机制。
Molecular mechanisms of α-synuclein and GBA1 in Parkinson's disease.
机构信息
The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave, Ward 12-369, Chicago, IL, 60611, USA.
出版信息
Cell Tissue Res. 2018 Jul;373(1):51-60. doi: 10.1007/s00441-017-2704-y. Epub 2017 Oct 24.
Abstract
Parkinson's disease (PD) is a neurodegenerative movement disorder characterized pathologically by the presence of Lewy bodies comprised of insoluble alpha (α)-synuclein. Pathological, clinical and genetic studies demonstrate that mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase) that is deficient in Gaucher's disease, are important risk factors for the development of PD. The molecular mechanism for the association between these two diseases is not completely understood. We discuss several possible mechanisms that may lead to GBA1-related neuronal death and α-synuclein accumulation including disruptions in lipid metabolism, protein trafficking and impaired protein quality control mechanisms. Elucidating the mechanism between GCase and α-synuclein may provide insight into potential therapeutic pathways for PD and related synucleinopathies.
摘要
帕金森病（PD）是一种神经退行性运动障碍，其病理学特征是存在由不溶性α-突触核蛋白组成的路易体。病理、临床和遗传研究表明，编码溶酶体酶葡萄糖脑苷脂酶（GCase）的 GBA1 基因突变，该酶在戈谢病中缺乏，是 PD 发展的重要危险因素。这两种疾病之间关联的分子机制尚不完全清楚。我们讨论了几种可能的机制，这些机制可能导致与 GBA1 相关的神经元死亡和α-突触核蛋白积累，包括脂质代谢、蛋白质运输和蛋白质质量控制机制受损的中断。阐明 GCase 和α-突触核蛋白之间的机制可能为 PD 和相关的突触核蛋白病提供潜在的治疗途径。
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本文引用的文献
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Exp Neurol. 2017 Dec;298(Pt B):191-201. doi: 10.1016/j.expneurol.2017.04.008. Epub 2017 Apr 23.
2
Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models.
Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2699-2704. doi: 10.1073/pnas.1616152114. Epub 2017 Feb 21.
3
Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease.
Biochem Soc Trans. 2016 Dec 15;44(6):1603-1610. doi: 10.1042/BST20160228.
4
Modulating ryanodine receptors with dantrolene attenuates neuronopathic phenotype in Gaucher disease mice.
Hum Mol Genet. 2016 Dec 1;25(23):5126-5141. doi: 10.1093/hmg/ddw322.
5
Parkinson disease-linked GBA mutation effects reversed by molecular chaperones in human cell and fly models.
Sci Rep. 2016 Aug 19;6:31380. doi: 10.1038/srep31380.
6
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7
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J Neurosci. 2016 Jul 13;36(28):7441-52. doi: 10.1523/JNEUROSCI.0636-16.2016.
8
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