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.

中文翻译：

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来自特发性帕金森病个体的 IL13 和 IL13RA1 中的两个单核苷酸多态性增加了细胞对氧化应激的易感性

白细胞介素 13 (IL-13) 及其受体 α1 (IL-13Rα1) 的人类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 中鉴定了两个罕见的单个 SNP，并测量了它们的细胞毒性作用。rs148077750 是 IL13 中的错义亮氨酸取代脯氨酸。它在患有早发性 PD 且没有其他已知单基因疾病形式的个体中发现，并且与 PD 显着相关（Fisher 精确检验：p 值 = 0.01，优势比 = 14.2）。rs145868092 是 IL13RA1 中亮氨酸对苯丙氨酸的取代，影响对 IL-13 结合至关重要的残基。这两种突变都增加了 IL-13 对暴露于亚致死剂量的过氧化氢、叔丁基过氧化氢或 RLS3（一种铁死亡诱导剂）的人类 SH-SY5Y 神经元的细胞毒活性。我们的数据显示，rs148077750 和 rs145868092 都赋予了功能获得性，这可能会增加患 PD 的风险。