Snx27 Deletion Promotes Recovery From Spinal Cord Injury by Neuroprotection and Reduces Macrophage/Microglia Proliferation.

Yuzhe Zeng,Bin Lin,Huaxi Xu,Jin Wu,Nawen Wang,Tiantian Guo,Xin Wang,Shuang Wang,Xi Li,Qiuyang Zheng,Songsong Wu,Zhida Chen

doi:10.3389/fneur.2018.01059

Abstract

Sorting nexin 27 (SNX27) is an endosome-associated cargo adaptor that is involved in various pathologies and development of neurological diseases. However, the role of SNX27 in spinal cord injury (SCI) remains unclear. In this study, we found that SNX27 was up-regulated in injured mice spinal cords by western blot and immunofluorescence. A comparative analysis of Basso mouse scale (BMS), footprint test and corticospinal tract (CST) tracing in Snx27+/+ and Snx27+/− mice revealed that haploinsufficiency of SNX27 ameliorated the clinical symptoms of SCI. Based on the results of western blot and immunofluorescence, mechanistically, we found that SNX27 deficiency suppresses apoptotic caspase-3 induced neuronal death. In addition, SNX27 haploinsufficiency lowers the infiltration and activation of macrophage/microglia by suppressing their proliferation at the SCI lesion site. Together, these results suggest that down-regulation of SNX27 is a potential therapy targeting both acute neuronal death and chronic neuroinflammation, and promoting nerve repair after SCI.

Highlights

Spinal cord injury (SCI) is a traumatic event resulting in sensory, motor, and autonomic dysfunction and has direct impacts on the quality of life of affected individuals [1], pharmacological treatments for SCI are still very limited [2]
Immunofluorescence analysis indicated that Sorting nexin 27 (SNX27) expression was strongly upregulated in SCI-groups compared to the sham-groups on day 7 postinjury (Figure 1C)
The expression of SNX27 was concentrated in the lesion site and was upregulated in the early stage of SCI, which suggests that SNX27 might have an impact on neuronal death and inflammation

Summary

Introduction

Spinal cord injury (SCI) is a traumatic event resulting in sensory, motor, and autonomic dysfunction and has direct impacts on the quality of life of affected individuals [1], pharmacological treatments for SCI are still very limited [2]. The underlying mechanisms are still largely unknown, many factors could be involved in this process [6]. Among these factors, excitotoxicity and neuroinflammation are two main mechanisms that cause the overall effects to the spinal cord [3]. Excitotoxicity is a kind of neuronal cell death caused by excessive activation of glutamate receptors due to increasing levels of extracellular glutamate at the lesion site. The increased activation of NMDA receptors contributes to extensive spinal dysfunction. Previous studies show that neuronal death due to CNS injury can be decreased by down-regulation of NMDA receptors such as GluN1 and GluN2B [7, 8]. Neuroinflammation responses involve inflammatory cell infiltration (such as neutrophils and macrophages), in addition to microglia activation

Methods

Results

Conclusion