Nemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS.

IF 13.3 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Journal of Clinical Investigation Pub Date : 2025-06-24 DOI:10.1172/JCI188138

Michael E Bekier, Emile S Pinarbasi, Gopinath Krishnan, Jack J Mesojedec, Madelaine Hurley, Harisankar Harikumar Sheela, Catherine A Collins, Layla T Ghaffari, Martina de Majo, Erik M Ullian, Mark Koontz, Sarah Coleman, Xingli Li, Elizabeth Mh Tank, Jacob Waksmacki, Fen-Biao Gao, Sami J Barmada

引用次数: 0

Abstract

Cytoplasmic TDP43 mislocalization and aggregation are pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the initial cellular insults that lead to TDP43 mislocalization remain unclear. In this study, we demonstrate that Nemo-like kinase (NLK) - a proline-directed serine/threonine kinase - promotes the mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are selectively elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, while genetic reduction of NLK reduces toxicity in human neuron models of ALS. Our findings suggest that NLK is a promising therapeutic target for neurodegenerative diseases.

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nemo样激酶在ALS中破坏核输入并驱动TDP43错定位。

细胞质TDP43错位和聚集是肌萎缩性侧索硬化症（ALS）的病理标志。然而，导致TDP43错误定位的初始细胞损伤尚不清楚。在这项研究中，我们证明了nemo样激酶(NLK) -一种脯氨酸导向的丝氨酸/苏氨酸激酶-通过破坏核输入促进TDP43和其他rna结合蛋白的错误定位。NLK水平在ALS患者组织中表现出TDP43错位的神经元中选择性升高，而NLK的遗传减少可降低ALS人神经元模型的毒性。我们的研究结果表明，NLK是神经退行性疾病的一个有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

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.