靶向特定激酶底物可缓解由克罗恩病相关LRRK2-N2081D变体诱导的加重的结肠炎严重程度。

IF 13.6 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
George R Heaton, Xingjian Li, Xianting Li, Xiaoting Zhou, Yuanxi Zhang, Duc Tung Vu, Marc Oeller, Ozge Karayel, Quyen Q Hoang, Meltem Ece Kars, Nitika Kamath, Minghui Wang, Leonid Tarassishin, Matthias Mann, Inga Peter, Zhenyu Yue
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引用次数: 0

摘要

LRRK2含有一个激酶结构域,其中N2081D克罗恩病(CD)风险和G2019S帕金森病(PD)致病变异位于该结构域。目前尚不清楚N2081D变异如何增加乳糜泻风险,以及这些相邻突变如何引起不同的疾病。为了研究cd链接的LRRK2 N2081D变异的病理生理学,我们建立了一个敲入(KI)小鼠模型,并将其与LRRK2- g2019s突变的影响进行了比较。与Lrrk2G2019S KI和WT小鼠相比,Lrrk2N2081D KI小鼠对诱导性结肠炎表现出更高的敏感性,导致更严重的肠道损伤。结肠组织分析显示,LRRK2 RAB底物磷酸化明显依赖突变,在Lrrk2N2081D小鼠中,磷酸化的RAB10水平显著升高。在细胞中,我们证明了N2081D突变通过不同于LRRK2- g2019s的机制激活LRRK2。我们还发现,促炎刺激增强了LRRK2激酶活性,导致树突状细胞(DCs)中RAB磷酸化和炎症反应的突变依赖性差异。最后,我们发现敲除Rab12,而不是药理学上的LRRK2激酶抑制,显著降低了Lrrk2N2081D小鼠结肠炎的严重程度。我们的研究描述了LRRK2相关CD的致病机制,强调了疾病相关LRRK2变异之间的结构和功能差异,并表明RAB蛋白是调节LRRK2活性的有希望的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting specific kinase substrates rescues increased colitis severity induced by the Crohn's disease-linked LRRK2-N2081D variant.

LRRK2 contains a kinase domain where the N2081D Crohn's disease (CD) risk and the G2019S Parkinson's disease (PD) pathogenic variants are located. It is not clear how the N2081D variant increases CD risk or how these adjacent mutations give rise to distinct disorders. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects with those of the LRRK2-G2019S mutation. Lrrk2N2081D KI mice demonstrated heightened sensitivity to induced colitis, resulting in more severe intestinal damage than in Lrrk2G2019S KI and WT mice. Analysis of colon tissue revealed distinct mutation-dependent LRRK2 RAB substrate phosphorylation, with significantly elevated phosphorylated RAB10 levels in Lrrk2N2081D mice. In cells, we demonstrated that the N2081D mutation activates LRRK2 through a mechanism distinct from that of LRRK2-G2019S. We also found that proinflammatory stimulation enhances LRRK2 kinase activity, leading to mutation-dependent differences in RAB phosphorylation and inflammatory responses in dendritic cells (DCs). Finally, we show that knockout of Rab12, but not pharmacological LRRK2 kinase inhibition, significantly reduced colitis severity in Lrrk2N2081D mice. Our study characterizes the pathogenic mechanisms of LRRK2-linked CD, highlights structural and functional differences between disease-associated LRRK2 variants, and suggests RAB proteins as promising therapeutic targets for modulating LRRK2 activity in CD treatment.

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来源期刊
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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