Targeting the Hippo pathway in Schwann cells ameliorates peripheral nerve degeneration via a polypharmacological mechanism.

Autor:	Chung HJ; Department of Anesthesiology and Pain Medicine, College of Medicine, Kosin University, Busan 49267, South Korea., Nguyen TNC; Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, South Korea., Lee JW; Department of Biology, College of Natural Sciences, Gangneung-Wonju National University, Gangneung 25457, South Korea., Huh Y; Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul 02447, South Korea., Ko S; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA., Lim H; Center for Scientific Instrumentation, Korea Basic Science Institute (KBSI), Cheongju 28119, South Korea., Seo H; New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (K-MEDI hub), Daegu 41061, South Korea., Ha YG; Department of Chemistry, College of Convergence Science, Kyonggi University, Suwon 16227, South Korea., Chang JH; Department of Biology Education, Kyungpook National University, Daegu 41566, South Korea., Woo JS; Department of Life Sciences, Korea University, Seongbuk-gu, Seoul 02841, South Korea., Song JJ; Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Yuseong-gu, Daejeon 34141, South Korea., Kim SW; Department of Pathology, College of Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul 02447, South Korea., Lee JS; Department of Neurology, College of Medicine, Kyung Hee University Hospital, Kyung Hee University, Seoul 02447, South Korea., Mo JS; Institute of Medical Science, School of Medicine, Ajou University, Suwon 16499, South Korea., Park B; Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea., Min KW; Department of Biology, College of Natural Sciences, Gangneung-Wonju National University, Gangneung 25457, South Korea., Yoon JH; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Oncology Science, College of Medicine, The University of Oklahoma, Oklahoma City, OK 73104, USA. Electronic address: jehyun-yoon@ouhsc.edu., Kim MS; Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, South Korea. Electronic address: mkim@dgist.ac.kr., Jung J; Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul 02447, South Korea. Electronic address: jjung@khu.ac.kr., Jeong NY; Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 49201, South Korea. Electronic address: jnyjjy@dau.ac.kr.
Jazyk:	angličtina
Zdroj:	Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics [Neurotherapeutics] 2024 Oct; Vol. 21 (6), pp. e00458. Date of Electronic Publication: 2024 Oct 08.
DOI:	10.1016/j.neurot.2024.e00458
Abstrakt:	Peripheral neuropathies (PNs) are common diseases in elderly individuals characterized by Schwann cell (SC) dysfunction and irreversible Wallerian degeneration (WD). Although the molecular mechanisms of PN onset and progression have been widely studied, therapeutic opportunities remain limited. In this study, we investigated the pharmacological inhibition of Mammalian Ste20-like kinase 1/2 (MST1/2) by using its chemical inhibitor, XMU-MP-1 (XMU), against WD. XMU treatment suppressed the proliferation, dedifferentiation, and demyelination of SCs in models of WD in vitro, in vivo, and ex vivo. As a downstream mediator of canonical and noncanonical Hippo/MST1 pathway activation, the mature microRNA (miRNA) let-7b and its binding partners quaking homolog (QKI)/nucleolin (NCL) modulated miRNA-mediated silencing of genes involved in protein transport. Hence, direct phosphorylation of QKI and NCL by MST1 might be critical for WD onset and pathogenesis. Moreover, p38α/mitogen-activated protein kinase 14 (p38α) showed a strong affinity for XMU, and therefore, it may be an alternative XMU target for controlling WD in SCs. Taken together, our findings provide new insights into the Hippo/MST pathway function in PNs and suggest that XMU is a novel multitargeted therapeutic for elderly individuals with PNs. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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