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Identification of an Alternatively Spliced α-Synuclein Isoform That Generates a 41-Amino Acid N-Terminal Truncated Peptide, 41-syn: Role in Dopamine Homeostasis.
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2018-07-25 , DOI: 10.1021/acschemneuro.8b00140
Ravali L Vinnakota , Deepthi Yedlapudi , Krishna Madhuri Manda , Keerti Bhamidipati , Kirthi Theja Bommakanti 1 , G Sree RangaLakshmi 1 , Shasi V Kalivendi
Affiliation  

The presynaptic protein, α-synuclein (α-syn), has been shown to play a crucial role in multiple neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and dementia with Lewy bodies (DLB). The three major domains of α-syn protein were shown to govern its membrane interaction, protein fibrillation, and chaperone activity. So far, four different alternatively spliced isoforms of α-syn, which lack either exon 3 (syn-126) or exon 5 (syn-112) or both (syn-98) resulting in altered function of the proteins, have been identified. In the present study, we have identified the smallest isoform of α-syn due to the skipping of exons 3 and 4 generating a 238 bp transcript. Due to the presence of a premature stop codon, the 238 bp transcript generated a 41 aa N-terminal peptide instead of the 78 aa protein, which is secreted into the extracellular medium when overexpressed in cells. The presence of 41-syn was initially noticed in the substantia nigra of PD autopsy tissues, as well as in cells undergoing oxidative stress. In vitro studies inferred that 41-syn neither aggregates nor alters the aggregation propensity of either WT or 112-syn. Overexpression of 41-syn or treatment of cells with 41-syn peptide did not affect cell viability. However, PC-12 cells treated with 41-syn exhibited a time and dose dependent enhancement in the cellular uptake of dopamine. Based on the physiological role of the N-terminal region of α-syn in modulating membrane trafficking events, we believe that the identification of 41-syn may provide novel impetus in unraveling the physiological basis of alternative splicing events in governing PD pathophysiology.

中文翻译:

生成41个氨基酸的N-末端截短的肽41-syn的另一种剪接的α-突触核蛋白同种型的鉴定:在多巴胺体内平衡中的作用。

突触前蛋白α-突触核蛋白(α-syn)已显示在多种神经退行性疾病中发挥关键作用,例如帕金森氏病(PD),阿尔茨海默氏病(AD)和路易体痴呆(DLB)。研究表明,α-syn蛋白的三个主要结构域决定着其膜相互作用,蛋白原纤化和伴侣活性。到目前为止,已经鉴定出缺少外显子3(syn-126)或外显子5(syn-112)或两者(syn-98)而导致蛋白质功能改变的α-syn的四种不同的可变剪接同工型。在本研究中,我们已经确定了由于外显子3和外显子4跳过而产生的238 bp转录本的最小的α-syn亚型。由于存在提前终止密码子,因此238 bp的转录本产生了41个氨基酸的N端肽,而不是78个氨基酸的蛋白,当在细胞中过度表达时,它会分泌到细胞外培养基中。最初在PD尸检组织的黑质以及经历氧化应激的细胞中发现了41-syn的存在。体外研究推断41-syn既不聚集也不改变WT或112-syn的聚集倾向。41-syn的过表达或用41-syn肽处理细胞均不影响细胞活力。但是,用41-syn处理的PC-12细胞在多巴胺的细胞摄取中表现出时间和剂量依赖性增强。基于α-syn的N末端区域在调节膜运输事件中的生理作用,我们认为41-syn的鉴定可能为揭示替代剪接事件在控制PD病理生理学的生理基础方面提供了新的动力。
更新日期:2018-07-11
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