The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson's Disease Model.
The Relationship between Iron and LRRK2 in a 6-OHDA-Induced Parkinson's Disease Model.
复制标题
6-OHDA 诱导的帕金森病模型中铁和 LRRK2 之间的关系。
DOI：
10.3390/ijms24043709
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发表时间：
2023-02-13
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
帕金森病(PD)的发病机制非常复杂，仍需进一步探讨。富含亮氨酸的重复蛋白激酶2(LRRK2)与家族性帕金森病的突变型和野生型的散发性帕金森病相关。PD患者黑质铁异常蓄积，但其确切作用尚不十分清楚。在这里，我们表明，右旋糖苷铁加剧了6-羟基多巴胺损伤大鼠的神经功能缺陷和多巴胺能神经元的丢失。6-OHDA和柠檬酸铁铵(FAC)显著提高LRRK2的活性，这体现在S935和S1292位的LRRK2的磷酸化。铁络合剂去铁胺可减弱6-OHDA诱导的LRRK2的磷酸化，尤其是在S1292位。6-OHDA和FAC通过激活LRRK2显著诱导促凋亡分子的表达和ROS的产生。此外，在WT-LRRK2组、G2019S-LRRK2组和无激酶活性的D2017A-LRRK2组中，具有高活性的G2019S-LRRK2对亚铁的吸收能力最强，细胞内铁含量最高。综上所述，我们的结果表明，铁促进了LRRK2的激活，而激活的LRRK2加速了铁的摄取，提示在多巴胺能神经元中存在铁和LRRK2之间的相互作用，为揭示帕金森病发生的潜在机制提供了新的视角。
The pathogenesis of Parkinson’s disease (PD) is very complex and still needs further exploration. Leucine-rich repeat kinase 2 (LRRK2) is associated with familial PD in mutant forms and sporadic PD in the wild-type form. Abnormal iron accumulation is found in the substantia nigra of PD patients, but its exact effects are not very clear. Here, we show that iron dextran exacerbates the neurological deficit and loss of dopaminergic neurons in 6-OHDA lesioned rats. 6-OHDA and ferric ammonium citrate (FAC) significantly increase the activity of LRRK2 as reflected by the phosphorylation of LRRK2, at S935 and S1292 sites. 6-OHDA-induced LRRK2 phosphorylation is attenuated by the iron chelator deferoxamine, especially at the S1292 site. 6-OHDA and FAC markedly induce the expression of pro-apoptotic molecules and the production of ROS by activating LRRK2. Furthermore, G2019S-LRRK2 with high kinase activity showed the strongest absorptive capacity for ferrous iron and the highest intracellular iron content among WT-LRRK2, G2019S-LRRK2, and kinase-inactive D2017A-LRRK2 groups. Taken together, our results demonstrate that iron promotes the activation of LRRK2, and active LRRK2 accelerates ferrous iron uptake, suggesting that there exists an interplay between iron and LRRK2 in dopaminergic neurons, providing a new perspective to uncover the underlying mechanisms of PD occurrence.
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