Phosphoglycerate Mutase 1 Prevents Neuronal Death from Ischemic Damage by Reducing Neuroinflammation in the Rabbit Spinal Cord.

Hyo Young Jung,Woosuk Kim,Yeo Sung Yoon,Kyu Ri Hahn,Dae Won Kim,In Koo Hwang,Hyun Jung Kwon,Seung Myung Moon

doi:10.3390/ijms21197425

Abstract

Phosphoglycerate mutase 1 (PGAM1) is a glycolytic enzyme that increases glycolytic flux in the brain. In the present study, we examined the effects of PGAM1 in conditions of oxidative stress and ischemic damage in motor neuron-like (NSC34) cells and the rabbit spinal cord. A Tat-PGAM1 fusion protein was prepared to allow easy crossing of the blood-brain barrier, and Control-PGAM1 was synthesized without the Tat peptide protein transduction domain. Intracellular delivery of Tat-PGAM1, not Control-PGAM1, was achieved in a time- and concentration-dependent manner. Immunofluorescent staining confirmed the intracellular expression of Tat-PGAM1 in NSC34 cells. Tat-PGAM1, but not Control-PGAM1, significantly alleviated H2O2-induced oxidative stress, neuronal death, mitogen-activated protein kinase, and apoptosis-inducing factor expression in NSC34 cells. After ischemia induction in the spinal cord, Tat-PGAM1 treatment significantly improved ischemia-induced neurological impairments and ameliorated neuronal cell death in the ventral horn of the spinal cord 72 h after ischemia. Tat-PGAM1 treatment significantly mitigated the ischemia-induced increase in malondialdehyde and 8-iso-prostaglandin F2α production in the spinal cord. In addition, Tat-PGAM1, but not Control-PGAM1, significantly decreased microglial activation and secretion of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α induced by ischemia in the ventral horn of the spinal cord. These results suggest that Tat-PGAM1 can be used as a therapeutic agent to reduce spinal cord ischemia-induced neuronal damage by lowering the oxidative stress, microglial activation, and secretion of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α.

Highlights

Spinal cord ischemia is a subject of high interest in the field of neuroscience, and the current research focuses on understanding the pathophysiology of neuronal death after ischemia and identifying preventive or therapeutic agents to overcome ischemia-related neuronal damage [1,2]
Phosphoglycerate mutase 1 (PGAM1) is highly susceptible to oxidative stress, which leads to the inhibition of glycolysis and is oxidized in conditions of neurological disease, such as Alzheimer’s disease and hypoxic damage [23,24,25]
PGAM1 levels are decreased in the brains of mice models of phenylketonuria [26] and in the hippocampus of mice exposed to copper toxicity [27]

Summary

Introduction

Spinal cord ischemia is a subject of high interest in the field of neuroscience, and the current research focuses on understanding the pathophysiology of neuronal death after ischemia and identifying preventive or therapeutic agents to overcome ischemia-related neuronal damage [1,2]. Several potential mechanisms underlying these events have been identified, such as energy depletion, oxidative stress, and the activation of inflammatory pathways after spinal cord ischemia [1,5,6,7,8]. The initial step in energy production from glucose is glycolysis. This process is controlled by phosphoglycerate mutase (PGAM) [E.C. 5.4.2.1], which catalyzes the interconversion of 2- and 3-phosphoglycerate [9,10]. Three isozymes (mm-, mb-, or bb-type) are present, classified based on the subunits of the PGAM dimer. Among these isozymes, mm- and bb-type isozymes are ubiquitously expressed in most tissues, including the brain, and mm- and mb-type isozymes are expressed in smooth, cardiac, and skeletal muscles. The brain form of PGAM (PGAM1) increases glycolysis in the brain and facilitates ATP production; oxidative modification inhibits glycolysis and, eventually, depletes ATP in the brain [11]

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Results

Conclusion