Cold‐inducible protein RBM3 mediates hypothermic neuroprotection against neurotoxin rotenone via inhibition on MAPK signalling

• Published in: Journal of cellular and molecular medicine Vol. 23; no. 10; pp. 7010 - 7020
• Main Authors: Yang, Hai‐Jie, Zhuang, Rui‐Juan, Li, Yuan‐Bo, Li, Tian, Yuan, Xin, Lei, Bing‐Bing, Xie, Yun‐Fei, Wang, Mian
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2019; John Wiley and Sons Inc
• Subjects: Activation; Alzheimer's disease; Apoptosis; Apoptosis - drug effects; Brain research; Cell Line, Tumor; Cell viability; Cold; Cold Temperature; Cytoprotection - drug effects; Cytotoxicity; Enzyme Activation - drug effects; Health risks; Humans; Hypothermia; Hypothermia, Induced; Immunoblotting; MAP kinase; MAP Kinase Signaling System - drug effects; MAPK signalling; Movement disorders; MPP; Neuroblastoma; Neurodegenerative diseases; Neuroprotection; Neuroprotection - drug effects; Neurotoxicity; Neurotoxins; Neurotoxins - toxicity; Original; Oxidative stress; Parkinson's disease; Proteins; RBM3; RNA-Binding Proteins - metabolism; Rot; Rotenone; Rotenone - toxicity; Studies; Viability; RBM3; rotenone; Parkinson's disease; MAPK signalling; hypothermia
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.14588

Mild hypothermia and its key product, cold‐inducible protein RBM3, possess robust neuroprotective effects against various neurotoxins. However, we previously showed that mild hypothermia fails to attenuate the neurotoxicity from MPP+, one of typical neurotoxins related to the increasing risk of Parkinson disease (PD). To better understand the role of mild hypothermia and RBM3 in PD progression, another known PD‐related neurotoxin, rotenone (ROT) was utilized in this study. Using immunoblotting, cell viability assays and TUNEL staining, we revealed that mild hypothermia (32°C) significantly reduced the apoptosis induced by ROT in human neuroblastoma SH‐SY5Y cells, when compared to normothermia (37°C). Meanwhile, the overexpression of RBM3 in SH‐SY5Y cells mimicked the neuroprotective effects of mild hypothermia on ROT‐induced cytotoxicity. Upon ROT stimulation, MAPK signalling like p38, JNK and ERK, and AMPK and GSK‐3β signalling were activated. When RBM3 was overexpressed, only the activation of p38, JNK and ERK signalling was inhibited, leaving AMPK and GSK‐3β signalling unaffected. Similarly, mild hypothermia also inhibited the activation of MAPKs induced by ROT. Lastly, it was demonstrated that the MAPK (especially p38 and ERK) inhibition by their individual inhibitors significantly decreased the neurotoxicity of ROT in SH‐SY5Y cells. In conclusion, these data demonstrate that RBM3 mediates mild hypothermia‐related neuroprotection against ROT by inhibiting the MAPK signalling of p38, JNK and ERK.