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

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

doi:10.3389/fcell.2020.00577

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

Front Cell Dev Biol. 2020 Jul 21:8:577. doi: 10.3389/fcell.2020.00577. eCollection 2020.

Authors

Liu-Lin Xiong^{1

2

3}, Yan-Xia Qin⁴, Qiu-Xia Xiao², Yuan Jin⁵, Mohammed Al-Hawwas³, Zheng Ma⁵, You-Cui Wang¹, Visar Belegu^{6

7}, Xin-Fu Zhou³, Lu-Lu Xue⁵, Ruo-Lan Du¹, Jia Liu⁵, Xue Bai², Ting-Hua Wang^{1

5

4}

Affiliations

¹ Institute of Neurobiological Disease, Department of Anesthesiology, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China.
² National Traditional Chinese Medicine Clinical Research Base and Western Medicine Translational Medicine Research Center, Department of Cardiac and Cerebral Diseases, Department of Anesthesiology, Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, China.
³ School of Pharmacy and Medical Sciences, Sansom Institute, Division of Health Sciences, University of South Australia, Adelaide, SA, Australia.
⁴ Department of Histology and Neurobiology, College of Preclinic and Forensic Medicine, Sichuan University, Chengdu, China.
⁵ Animal Zoology Department, Institute of Neuroscience, Kunming Medical University, Kunming, China.
⁶ International Center for Spinal Cord Injury, Kennedy Krieger Institute, Baltimore, MD, United States.
⁷ Department of Neurology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

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.

Keywords: PDXK; RNA interference; microRNA339; motor cortex plasticity; spinal cord injury.

Grants and funding

S10 OD021567/OD/NIH HHS/United States