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

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.

Anti‐inflammatory effects of hypoxia‐preconditioned human periodontal ligament cell secretome in an experimental model of multiple sclerosis: a key role of IL‐37

“…An accumulation of evidence in recent years argues that reactive nitrogen species are among the major intracellular signal transducers that support pleiotropic responses that range from autophagy to death (51, 52). Dysregulation of autophagy is recognized as playing a central role in several neurodegenerative diseases (53, 54); however, its role in MS remains unclear (55). Although some early studies consider autophagy to be a mechanism of cell death, in recent years, has emerged in hypothesis as a useful mechanism for protecting cells from apoptosis (56).…”

“…In addition, given the increasing evidence that autophagy has substantial effects on the immune system, it would not be surprising if this process was involved in the IL-37–mediated immunosuppression in MS. Here, to explore the involvement of autophagy, we examined the expression of two key autophagic proteins, beclin-1 and LC3, which have previously been detected in the spinal cord from mice with EAE (55). In agreement with this, we observed a down-regulation of beclin-1 and LC3 expression in mice with EAE, which was conversely enhanced after H-hPDLSCs-CM treatment.…”

Lysosomes as a therapeutic target

“…Increased levels of macroautophagy markers were measured in the blood and brain of patients with MS 122,132 . However, impaired macroautophagy was found in the spinal cord of experimental autoimmune encephalomyelitis mice 133 . In a rat model mimicking human CIDP, both macro autophagy and CMA processes were found to be hyper activated in lymphatic system cells and non neuronal cells (sciatic nerves) of peripheral nervous system cells 59 .…”

Real-state of autophagy signaling pathway in neurodegenerative disease; focus on multiple sclerosis

“…For example, the up-regulation of autophagy by mTOR inhibitors such as rapamycin protects the cells against neuro-degeneration in mice model [50]. Feng et al disclosed that defective autophagy is linked to neuronal injury in a mouse model of MS [51]. The protective effect is not only a function of autophagy releasing fuels for cells, but also appears to be associated to decrease in the amount of intracellular mitochondria (mitophagy rate).…”