Multiple sclerosis is a chronic inflammatory demyelinating disorder of the central nervous system. Myelin is a multilayered membrane sheath that regulates the metabolic transfer from oligodendrocytes to axons and rapid impulse propagation. Oligodendrocytes are large glial cells that create myelin sheath needed for neuronal axons. Oligodendrocytes are implicated with many neurological diseases such as Parkinson’s disease, ALS, and TBI. For multiple sclerosis (MS), onset occurs around 20-40 years with a high incidence in women, and is characterized by muscle weakness and numbness. MS does not have a cure, however there are disease modifying treatments that can limit new disease activity and reduce progress or onset of disability, and there is a CNS protective strategy.
In the paper titled, Prolonging the integrated stress response enhances CNS remyelination in an inflammatory environment, by Dr. Chen et al., they investigate how the inflammatory environment of demyelinated lesions in multiple sclerosis (MS) can contribute to remyelination failure. The integrated stress response (ISR) plays a key role in the response of oligodendrocytes to CNS inflammation. They expand further on the idea that Sephin1 enhances the ISR and Sephin1 treatment protects mature oligodendrocytes, diminishes demyelination and delays clinical symptoms in the mouse model. In this study, they examined the effect of genetic or pharmacological ISR enhancement on remyelination oligodendrocytes and the remyelination process in the presence of inflammation. They used the experimental autoimmune encephalomyelitis (EAE) and cuprizone induced demyelination model on double transgenic mice expressing IFN-ɣ, a cytokine that stimulates inflammatory aspects of MS. Additionally, researchers examined the coupling of Sephin1 and bazedoxifene (BZA) on remyelination. When examining Sephin1 treatment on EAE mice, they found that there was an increased density in remyelinated axons in the mice treated with Sephin1 as compared to the mice with the vehicle treatment. This suggests that Sephin1 promotes remyelination in an EAE environment. Researchers then examined whether the Gadd34 mutation promotes oligodendrocyte survival in the presence of IFN-ɣ during demyelination/remyelination in the cuprizone model. They found that in the control mice there was a significant number of axons displaying myelin sheath loss. Also both wild-type mice and KO-double transgenic mice presented with reduced levels of myelinated axons in the presence of IFN-ɣ. Then there was no difference between the percent of myelinated axons between IFN-ɣ+ and IFN-ɣ- mice. After cuprizone withdrawal both IFN-ɣ oppressed WT and KO mice showed spontaneous myelination. Then remyelination was suppressed in the corpus callosum of WT IFN-ɣ-expressing mice, but not KO IFN-ɣ-expressing mice. This suggests that prolonging ISR can result in increased repopulation of oligodendrocytes and remyelination following demyelination in the presence of IFN-ɣ. Lastly, they examined the combined treatment of Sephin1 and BZA in remyelination in the presence of IFN-ɣ. They found that mice with the combined treatment had a significant increase in the myelinated axons as compared to the mice with the vehicle treatment. The findings from this study highlight the significance of Sephin1 and the ISR in the treatment for those suffering with MS.
In the paper titled, Connexins in oligodendrocytes and astrocytes: Possible factors for demyelination in multiple sclerosis, by Dr. Zhang, et al., they investigate the role of connexins in the demyelination process and the mechanisms by which connexins regulate myelination. Connexin deficiency or mutations are implicated in a familiar pathology in patients with MS or MS animal models. Cx32 is a connexin that is distributed in the oligodendrocytes and when the Cx32 gene was removed from mice, these mice expressed a progressive demyelinating neuropathy, indicating that Cx32 deficiency may be a risk factor for MS. Next, when examining the idea that multiple connexin deficiencies contribute to more serious myelin damage, they found that there was an increased inflammatory response. Additionally, the loss of function of two connexins in oligodendrocytes led to a more severe myelin damage as compared to the loss of function of two connexins in astrocytes. When examining the gray matter in MS patients, there was a decrease in the Cx32 and Cx47 gap functions. Next, researchers utilized the EAE model in mice and found that EAE mice with knockout Cx47 had much more severe myelin and axonal loss as compared the Cx32 knockout mice and wild type mice. Lastly, the connectivity between OPCs and oligodendrocytes and between OPCs and oligodendrocytes is also altered in MS patients. OPCs that migrate into MS normal-appearing gray matter differentiate into mature oligodendrocytes to initiate remyelination. These OPCs had enhanced expression of Cx47, while there were fewer Cx43 gap junctions surrounding OPCs. The connectivity between OPCs and astrocytes may be disturbed which can lead to failure of remyelination. This study highlights the crucial role of connexins in glial cells as well as how they regulate the development and maintenance of myelin.
While both of these articles focus on MS, they focus on different mechanisms that are implicated with MS. The first study focuses on the integrated stress response and how it can influence the inflammatory environment of demyelinated lesions in MS. While the second study focuses on the role of connexins in the demyelination process and the mechanism by which they regulate myelination. Both utilize the EAE model to further their investigations in MS and examine the mechanisms that are contributing to MS. It is interesting to see how there are multiple different cellular processes that can all influence myelination and demyelination. The studies approach MS with a similar focus yet different approaches and it highlights how this disease has many different influences. These articles play a crucial role in uncovering more about MS, which can lead to pharmacological treatments and other therapeutic benefits that can help alleviate those suffering with this disease.
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