Targeting the Hippo pathway in Schwann cells ameliorates peripheral nerve degeneration via a polypharmacological mechanism
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.
Authors
- Heejin Lim (ORCID: https://orcid.org/0000-0002-5436-709X)
- Je‐Hyun Yoon (ORCID: https://orcid.org/0000-0001-7615-8654)
- Jeong Ho Chang (ORCID: https://orcid.org/0000-0002-2126-0317)
- Seungbeom Ko (ORCID: https://orcid.org/0000-0002-8457-3134)
- Ji‐Joon Song (ORCID: https://orcid.org/0000-0001-7120-6311)
- Kyung‐Won Min
- Junyang Jung (ORCID: https://orcid.org/0000-0003-3946-5406)
- Jae‐Sung Woo (ORCID: https://orcid.org/0000-0001-9163-3433)
- Hyung-Joo Chung (ORCID: https://orcid.org/0000-0001-9545-3245)
- Jin San Lee (ORCID: https://orcid.org/0000-0002-5017-854X)
- Min‐Sik Kim (ORCID: https://orcid.org/0000-0001-7317-5360)
- Thy N. C. Nguyen
- Boyoun Park (ORCID: https://orcid.org/0000-0003-4119-3649)
- So‐Woon Kim (ORCID: https://orcid.org/0000-0002-9840-848X)
- Na Young Jeong (ORCID: https://orcid.org/0000-0003-2130-4719)
- Ji Won Lee (ORCID: https://orcid.org/0000-0001-8680-8673)
- Hyewon Seo
- Jung-Soon Mo
- Young-Geun Ha
- Youngbuhm Huh
Institutions
- Gangneung–Wonju National University (KR)
- Medical University of South Carolina (US)
- Korea Advanced Institute of Science and Technology (KR)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Yonsei University (KR)
- Korea University (KR)
- Kyonggi University (KR)
- Kyungpook National University (KR)
- Kyung Hee University (KR)
- Korea Basic Science Institute (KR)
- Daegu-Gyeongbuk Medical Innovation Foundation (KR)
- Ajou University (KR)
- Kosin University (KR)
Publication Details
- Journal
- Neurotherapeutics
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.neurot.2024.e00458
- Citations
- 4
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 1.30
Funders
- Medical University of South Carolina
- University of Oklahoma
- University of South Carolina
- National Research Foundation
- Ministry of Science, ICT and Future Planning
- National Research Foundation of Korea
- Daegu Gyeongbuk Institute of Science and Technology
- University of Oklahoma Health Sciences Center