Defective autophagy is associated with neuronal injury in a mouse model of multiple sclerosis

Xuedan Feng,Huiqing Hou,Yueli Zou,Li Guo

doi:10.17305/bjbms.2017.1696

Abstract

Neurodegeneration, along with inflammatory demyelination, is an important component of multiple sclerosis (MS) pathogenesis. Autophagy is known to play a pivotal role in neuronal homeostasis and is implicated in several neurodegenerative disorders. However, whether autophagy is involved in the mechanisms of neuronal damage during MS remains to be investigated. Experimental autoimmune encephalomyelitis (EAE), an in vivo model of MS, was induced in female C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein p35-55. After that, autophagic flux in the spinal cord of mice was evaluated by detection of LC3-II and Beclin1 protein expressions. EAE mice were then administered with rapamycin and 3-methyladenine (3-MA) for 10 days. Afterward, the changes in LC3-II, Beclin1, and p62 expression, number of infiltrated inflammatory cells, demyelinated lesion area, and neuronal damage, as well as clinical scores, were assessed. Further, apoptotic cell rate and apoptosis-related protein expressions were monitored. We observed an impaired autophagic flux and increased neuronal damage in the spinal cords of EAE mice. We also found that rapamycin, an autophagy inducer, mitigated EAE-induced autophagy decrease, inflammation, demyelination and neuronal injury, as well as the abnormal clinical score. In addition, rapamycin suppressed cell apoptosis, and decreased Bax/Bcl-2 ratio and cleaved caspase-3 expression. Conversely, the effect of autophagy inhibitor 3-MA on EAE mice resulted in completely opposite results. These results indicated that autophagy deficiency, at least in part, contributed to EAE-induced neuronal injury and that pharmacological modulation of autophagy might be a therapeutic strategy for MS.

Highlights

Multiple sclerosis (MS) is traditionally regarded as a T-cellmediated autoimmune disorder of the central nervous system that is morphologically characterized by inflammatory demyelination, astrogliosis, and neuroaxonal degeneration [1]
LC3-II is closely associated with autophagosome number, and Beclin1 is well known as autophagy-related gene
The level of Beclin1 was downregulated in EAE mice but it was reversed to control level at the 30th day, as compared with control group (Figure 1C and D)

Summary

Introduction

Multiple sclerosis (MS) is traditionally regarded as a T-cellmediated autoimmune disorder of the central nervous system that is morphologically characterized by inflammatory demyelination, astrogliosis, and neuroaxonal degeneration [1]. Aside from inflammatory neurotoxicity, neurodegeneration is associated with certain inflammation-independent mechanisms such as oxidative stress, axoplasmic Ca2+ accumulation, glutamate excitotoxicity, mitochondrial dysfunction, and protein aggregation and carbonylation. Known as macroautophagy, is a lysosome-mediated degradation pathway through which cells engulf and transport superfluous or impaired organelles, mis/unfolded proteins, and invading microorganisms to the lysosomes for degradation. In recent years, both in vivo and in vitro findings have shown that autophagy is a critical mediator of inflammation and immunity [3,4]. Impaired autophagy fails to eliminate proteins that are prone to aggregation, leading to neuronal cell damage and death [7,8]. Intervention of autophagy might affect the onset and progress of neurodegeneration in MS

Methods

Results

Conclusion