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扩增型和野生型ataxin-3改变过表达α-突触核蛋白的SH-SY5Y细胞的氧化还原状态。

Expanded and Wild-type Ataxin-3 Modify the Redox Status of SH-SY5Y Cells Overexpressing α-Synuclein.

作者信息

Noronha Carolina, Perfeito Rita, Laço Mário, Wüllner Ullrich, Rego A Cristina

机构信息

Faculty of Medicine, University of Coimbra, Coimbra, Portugal.

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

出版信息

Neurochem Res. 2017 May;42(5):1430-1437. doi: 10.1007/s11064-017-2199-7. Epub 2017 Feb 25.

Abstract

Neurodegenerative diseases are considered to be distinct clinical entities, although they share the formation of proteinaceous aggregates and several neuropathological mechanisms. Increasing evidence suggest a possible interaction between proteins that have been classically associated to distinct neurodegenerative diseases. Thus, common molecular and cellular pathways might explain similarities between disease phenotypes. Interestingly, the characteristic Parkinson's disease (PD) phenotype linked to bradykinesia is also a clinical presentation of other neurodegenerative diseases. An example is Machado-Joseph disease (MJD), with some patients presenting parkinsonism and a positive response to levodopa (L-DOPA). Protein aggregates positive for α-synuclein (α-Syn), a protein associated with PD, in the substantia nigra of MJD models made us hypothesize a putative additive biological effect induced by expression of α-Syn and ataxin-3 (Atx3), the protein affected in MJD. Hence, in this study we analysed the influence of these two proteins (α-Syn and wild-type or mutant Atx3) on modified redox signaling, a pathological process potentially linked to both diseases, and also the impact of exposure to iron and rotenone in SH-SY5Y neuroblastoma cells. Our results show that both α-Syn and mutant Atx3 overexpression per se increased oxidation of dichlorodihydrofluorescein (DCFH), and co-expression of these proteins exhibited additive effect on intracellular oxidation, with no correlation with apoptotic features. Mutant Atx3 and α-Syn also potentiated altered redox status induced by iron and rotenone, a hint to how these proteins might influence neuronal dysfunction under pro-oxidant conditions. We further show that overexpression of wild-type Atx3 decreased intracellular DCFH oxidation, possibly exerting a neuroprotective role.

摘要

神经退行性疾病被认为是不同的临床实体,尽管它们都存在蛋白质聚集体的形成以及一些神经病理机制。越来越多的证据表明,传统上与不同神经退行性疾病相关的蛋白质之间可能存在相互作用。因此,共同的分子和细胞途径可能解释疾病表型之间的相似性。有趣的是,与运动迟缓相关的典型帕金森病(PD)表型也是其他神经退行性疾病的临床表现。一个例子是马查多-约瑟夫病(MJD),一些患者表现出帕金森综合征且对左旋多巴(L-DOPA)有阳性反应。在MJD模型的黑质中,对与PD相关的蛋白质α-突触核蛋白(α-Syn)呈阳性的蛋白质聚集体,使我们推测α-Syn和ataxin-3(Atx3,在MJD中受影响的蛋白质)的表达可能产生一种叠加的生物学效应。因此,在本研究中,我们分析了这两种蛋白质(α-Syn和野生型或突变型Atx3)对修饰的氧化还原信号传导的影响,氧化还原信号传导是一种可能与这两种疾病都相关的病理过程,同时还分析了在SH-SY5Y神经母细胞瘤细胞中暴露于铁和鱼藤酮的影响。我们的结果表明,α-Syn和突变型Atx3的过表达本身都会增加二氯二氢荧光素(DCFH)的氧化,并且这些蛋白质的共表达对细胞内氧化具有叠加效应,与凋亡特征无关。突变型Atx3和α-Syn还增强了由铁和鱼藤酮诱导的氧化还原状态改变,这提示了这些蛋白质在促氧化条件下可能影响神经元功能障碍的方式。我们进一步表明,野生型Atx3的过表达降低了细胞内DCFH的氧化,可能发挥神经保护作用。

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