Aminosalicylic acid reduces ER stress and Schwann cell death induced by MPZ mutations

Chang,Eun   Hyuk; Mo,Won   Min; Doo,Hyun   Myung; Lee,Ji‑Su; Park,Hwan   Tae; Choi,Byung‑Ok; Hong,Young   Bin

doi:10.3892/ijmm.2019.4178

Aminosalicylic acid reduces ER stress and Schwann cell death induced by MPZ mutations

Authors:
- Eun Hyuk Chang
- Won Min Mo
- Hyun Myung Doo
- Ji‑Su Lee
- Hwan Tae Park
- Byung‑Ok Choi
- Young Bin Hong
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Affiliations: Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Co., Ltd., Seoul 06351, Republic of Korea, Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea, Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 03063, Republic of Korea , Department of Physiology, College of Medicine, Dong‑A University, Busan 49201, Republic of Korea, Department of Biochemistry, College of Medicine, Dong‑A University, Busan 49201, Republic of Korea
Published online on: May 2, 2019 https://doi.org/10.3892/ijmm.2019.4178
Pages: 125-134
Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mutations in myelin protein zero (MPZ) cause inherited peripheral neuropathies, including Charcot‑Marie‑Tooth disease (CMT) and Dejerine‑Sottas neuropathy. Mutant MPZ proteins have previously been reported to cause CMT via enhanced endoplasmic reticulum (ER) stress and Schwann cell (SC) death, although the pathological mechanisms have not yet been elucidated. In this study, we generated an in vitro model of rat SCs expressing mutant MPZ (MPZ V169fs or R98C) proteins and validated the increase in cell death and ER stress induced by the overexpression of the MPZ mutants. Using this model, we examined the efficacy of 3 different aminosalicylic acids (ASAs; 4‑ASA, sodium 4‑ASA and 5‑ASA) in alleviating pathological phenotypes. FACS analysis indicated that the number of apoptotic rat SCs, RT4 cells, induced by mutant MPZ overexpression was significantly reduced following treatment with each ASA. In particular, treatment with 4‑ASA reduced the levels of ER stress markers in RT4 cells induced by V169fs MPZ mutant overexpression and relieved the retention of V169fs mutant proteins in the ER. Additionally, the level of an apoptotic signal mediator (p‑JNK) was only decreased in the RT4 cells expressing R98C MPZ mutant protein following treatment with 4‑ASA. Although 4‑ASA is known as a free radical scavenger, treatment with 4‑ASA in the in vitro model did not moderate the level of reactive oxygen species, which was elevated by the expression of mutant MPZ proteins. On the whole, the findings of this study indicate that treatment with 4‑ASA reduced the ER stress and SC death caused by 2 different MPZ mutants and suggest that ASA may be a potential therapeutic agent for CMT.

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