MicroRNA339 Targeting PDXK Improves Motor Dysfunction and Promotes Neurite Growth in the Remote Cortex Subjected to Spinal Cord Transection.

Liu-Lin Xiong,Mohammed Al-Hawwas,Yuan Jin,Xin-Fu Zhou,Xue Bai,Jia Liu,Lu-Lu Xue,You-Cui Wang,Zheng Ma,Ting-Hua Wang,Ruo-Lan Du,Visar Belegu,Yan-Xia Qin,Qiu-Xia Xiao

doi:10.3389/fcell.2020.00577

Abstract

Spinal cord injury (SCI) is a fatal disease that can cause severe disability. Cortical reorganization subserved the recovery of spontaneous function after SCI, although the potential molecular mechanism in this remote control is largely unknown. Therefore, using proteomics analysis, RNA interference/overexpression, and CRISPR/Cas9 in vivo and in vitro, we analyzed how the molecular network functions in neurological improvement, especially in the recovery of motor function after spinal cord transection (SCT) via the remote regulation of cerebral cortex. We discovered that the overexpression of pyridoxal kinase (PDXK) in the motor cortex enhanced neuronal growth and survival and improved locomotor function in the hindlimb. In addition, PDXK was confirmed as a target of miR-339 but not miR-124. MiR-339 knockout (KO) significantly increased the neurite outgrowth and decreased cell apoptosis in cortical neurons. Moreover, miR-339 KO rats exhibited functional recovery indicated by improved Basso, Beattie, and Bresnehan (BBB) score. Furthermore, bioinformatics prediction showed that PDXK was associated with GAP43, a crucial molecule related to neurite growth and functional improvement. The current research therefore confirmed that miR-339 targeting PDXK facilitated neurological recovery in the motor cortex of SCT rats, and the underlying mechanism was associated with regulating GAP43 in the remote cortex of rats subjected to SCT. These findings may uncover a new understanding of remoting cortex control following SCI and provide a new therapeutic strategy for the recovery of SCI in future clinical trials.

Highlights

Spinal cord injury (SCI) in the shape of hemisection, transection, or crushes cause body movement and sensory and autonomic dysfunction (Courtine et al, 2008; Kao et al, 2009; Yunta et al, 2012; Hu et al, 2013; Chang et al, 2018)
In our research, applying a two-dimensional differential in-gel electrophoresis (2D-DIGE) and the tandem mass spectrometry (MS/MS) method, we found that the level of pyridoxal kinase (PDXK) was significantly increased in the motor cortex of rats after spinal cord transection (SCT)
Our study reported that miR-339 is crucial for PDXK function in the remote cortex subjected to SCT, which may provide a potential strategy for SCT therapy in future clinical trials

Summary

Introduction

Spinal cord injury (SCI) in the shape of hemisection, transection, or crushes cause body movement and sensory and autonomic dysfunction (Courtine et al, 2008; Kao et al, 2009; Yunta et al, 2012; Hu et al, 2013; Chang et al, 2018). As one of the most severe SCI, spinal cord transection (SCT) can result in serious disability and bring about debilities both medically and socioeconomically (Liu et al, 2014; Nas et al, 2015). Previous reports indicated that SCI influences the somatotopic organization of the primary somatosensory cortex, evoking changes in the cortical networks that play a critical role in cortical reorganization after SCI (Kao et al, 2009; Aguilar et al, 2010). Investigating the underlying mechanism of the remote cortex in SCI may provide a new strategy to promote the recovery of SCI and potentially contribute to clinical practice

Methods

Results

Conclusion