Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson's disease increase cellular susceptibility to oxidative stress.
Two single nucleotide polymorphisms in IL13 and IL13RA1 from individuals with idiopathic Parkinson's disease increase cellular susceptibility to oxidative stress.
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DOI：
10.1016/j.bbi.2020.04.007
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发表时间：
2020-08
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影响因子：
--
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人类白细胞介素13(IL-13)及其受体α1(IL-13Rα1)基因位于与帕金森病(PD)相关的染色体区域。IL-13与其受体的相互作用增加了小鼠多巴胺能神经元对氧化应激的敏感性。我们在IL13和IL13RA1中发现了两个罕见的单一SNP，并检测了它们的细胞毒作用。Rs148077750是IL13中亮氨酸到脯氨酸的错义替换。该基因在早发性帕金森病患者中被发现，且与帕金森病显著相关(Fisher‘s Exact检验：P值=0.01，优势比=14.2)。Rs145868092是IL13RA1中亮氨酸到苯丙氨酸的替代，影响IL-13结合的关键残基。这两个突变都增加了IL-13对暴露于亚致死剂量的过氧化氢、叔丁基氢过氧化氢或铁下垂诱导剂RLS3的人SH-SY5Y神经元的细胞毒活性。我们的数据显示，rs148077750和rs145868092都具有可能增加帕金森病发病风险的功能增益。
The human genes for Interleukin 13 (IL-13) and its receptor alpha 1 (IL-13Rα1) are in chromosomal regions associated with Parkinson’s disease (PD). The interaction of IL-13 with its receptor increases the susceptibility of mouse dopaminergic neurons to oxidative stress. We identified two rare single SNPs in IL13 and IL13RA1 and measured their cytotoxic effects. rs148077750 is a missense leucine to proline substitution in IL13. It was found in individuals with early onset PD and no other known monogenic forms of the disease and is significantly linked with PD (Fisher’s exact test: p-value=0.01, odds ratio=14.2). rs145868092 is a leucine to phenylalanine substitution in IL13RA1 affecting a residue critical for IL-13 binding. Both mutations increased the cytotoxic activity of IL-13 on human SH-SY5Y neurons exposed to sublethal doses of hydrogen peroxide, t-butyl hydroperoxide or RLS3, an inducer of ferroptosis. Our data show that both rs148077750 and rs145868092 conferred a gain-of-function that may increase the risk of developing PD.
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影响因子：
7
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