Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson's Disease and Potential Therapeutic Role of 5' Untranslated Region-Directed Small Molecules.
Alpha-Synuclein in Alcohol Use Disorder, Connections with Parkinson's Disease and Potential Therapeutic Role of 5' Untranslated Region-Directed Small Molecules.
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α-核蛋白在酒精使用障碍中，与帕金森氏病的联系以及5'未翻译区域指导的小分子的潜在治疗作用。
DOI：
10.3390/biom10101465
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发表时间：
2020-10-21
期刊：
影响因子：
5.5
通讯作者：
Rogers JT
中科院分区：
文献类型：
--
作者：
Cahill CM;Aleyadeh R;Gao J;Wang C;Rogers JT
α-突触核蛋白(α-Syn)是由突触核蛋白α-SNCA基因编码的一个140aa的蛋白质。它是与帕金森病(PD)相关的突触蛋白，也是与PD和其他阿尔法突触核病(包括路易体痴呆(LBD)和多系统萎缩(MSA)相关的路易小体中表达最高的蛋白质。铁沉积存在于刘易体的核心，有报道表明，包括Cu2+和Fe2+在内的二价金属离子增强了α-Syn的聚集。α-Syn的差异表达与酒精使用障碍有关，特定的基因变异导致酒精中毒的风险，包括酒精渴望。α-Syn的剪接变体导致几种更容易聚集的较短形式的表达，与PD和AUD都相关，常见的转录变体可能能够预测一些运动障碍或PD亚型的高危人群，包括继发性帕金森综合征。PD和AUD都与肝脏和脑铁代谢紊乱有关。过去十年的研究表明，α-Syn具有铁输入功能，能够将铁的Fe3+氧化为Fe2+，从而促进其进入细胞。我们之前的研究已经在α-Syn mRNA的5‘非翻译区(5’Utr)发现了一个铁反应元件(IRE)，我们已经使用α-Syn 5‘Utr来筛选调节其在H4神经细胞系中表达的小分子。这些筛选使我们发现了几个有趣的小分子，它们既能降低和增加α-syn的表达，也可能与最近描述的间充质干细胞疗法一起，使酒精和帕金森病大脑不同区域的α-syn表达正常化。
Alpha-synuclein (α-Syn) is a 140-amino acid (aa) protein encoded by the Synuclein alpha SNCA gene. It is the synaptic protein associated with Parkinson’s disease (PD) and is the most highly expressed protein in the Lewy bodies associated with PD and other alpha synucleopathies, including Lewy body dementia (LBD) and multiple system atrophy (MSA). Iron deposits are present in the core of Lewy bodies, and there are reports suggesting that divalent metal ions including Cu2+ and Fe2+ enhance the aggregation of α-Syn. Differential expression of α-Syn is associated with alcohol use disorder (AUD), and specific genetic variants contribute to the risk for alcoholism, including alcohol craving. Spliced variants of α-Syn, leading to the expression of several shorter forms which are more prone to aggregation, are associated with both PD and AUD, and common transcript variants may be able to predict at-risk populations for some movement disorders or subtypes of PD, including secondary Parkinsonism. Both PD and AUD are associated with liver and brain iron dyshomeostasis. Research over the past decade has shown that α-Syn has iron import functions with an ability to oxidize the Fe3+ form of iron to Fe2+ to facilitate its entry into cells. Our prior research has identified an iron-responsive element (IRE) in the 5’ untranslated region (5’UTR) of α-Syn mRNA, and we have used the α-Syn 5’UTR to screen for small molecules that modulate its expression in the H4 neuronal cell line. These screens have led us to identify several interesting small molecules capable of both decreasing and increasing α-Syn expression and that may have the potential, together with the recently described mesenchymal stem cell therapies, to normalize α-Syn expression in different regions of the alcoholic and PD brain.
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