Wednesday, April 30, 2025

A Glimpse of the (M)i(S)sing Cure

There are many neurodegenerative diseases, with some common ones being Alzheimer’s disease, Parkinson’s diseases, and multiple sclerosis (MS). These are characterized by the irreversible deterioration of neurons in the central nervous system that can lead to a multitude of symptoms. Multiple sclerosis in particular is a chronic and unpredictable autoimmune disorder. This means it causes the body’s immune system to target and attack the myelin sheath of neurons, leading to a disruption of communication between the brain and the body. There is currently no cure for this disease, but there are many works of research that are in the progress of trying to find possible treatments for MS patients and possible prevention for MS development. 

Inflammation was found to impair the ability of oligodendrocyte precursor cells (OPC) to mature and remyelinate axons, contributing to the possible causes of multiple sclerosis. However, it was found that there was a way to protect oligodendrocytes and enhance myelination in Yanan Chen’s research titled, “Insights into the mechanism of oligodendrocyte protection and remyelination enhancement by the integrated stress response.” In this study, she and her colleagues found that activating the Integrated Stress Response (SR) with compounds like Sephin1 and bazedoxifene (BZA) were able to accelerate remyelination even under inflammation. These findings suggested that a combination therapy targeting both the ISR pathway and OPC differentiation could possibly restore and enhance neuronal functions in patients with multiple sclerosis. Essentially, a way to overcome inflammatory damage was found but preparing these oligodendrocyte precursor cells for myelination does not mean they have the necessary means for the actual repairing process.

Certain resources are required for remyelination to occur and a finding related to such is that cholesterol biosynthesis is one of these critical requirements for remyelination to occur. Rhonda Voskuhl’s work titled, “Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis,” found that oligodendrocytes upregulate cholesterol synthesis genes during remyelination and that the activation of estrogen receptor-beta (ERβ) enhances remyelination as well. This review presents another possible therapeutic strategy that could be used as treatment for myelin repair in MS patients. If clinically proven to be able to be done, targeting ERβ could boost remyelination, as it was found to amplify the expression of the cholesterol synthesis genes that were being upregulated during remyelination.

By utilizing both of these studies and doing further research until it reaches clinical human trials, it is possible that treatment for multiple sclerosis may be achieved if all goes well and side effects are not too risky. Dr. Chen’s research allows for a way to protect OPCs so that they are able to be prepared to be differentiated into myelinating oligodendrocytes even under inflammation where they are getting damaged, by targeting the ISR with Sephin1 and BZA. This serves almost as a template for Dr. Voskuhl’s study of what resources are then needed to repair the myelin sheaths after the damage once they are differentiated. Combining both of these research studies suggest possible therapeutic processes that could be used to help treat MS patients, showcasing that they must counteract or overcome inflammation and support the metabolic demands regarding the resources needed during remyelination. Both studies fundamentally highlight the importance of directly supporting oligodendrocytes as a whole rather than focusing on different aspects of it, such as only looking to enhance remyelination but not looking to see if it has the resources to do so. Perhaps, future research could combine these two in a way where they are investigated together to see how everything would work out cohesively and how this could be applied to actual patients, or to see what is missing from being able to develop treatment. Ultimately, the ongoing research on multiple sclerosis and the possible pathways that could be targeted in order to find a cure is going relatively well with new findings that support and help these professionals get closer to being able to treat this unpredictable and debilitating disease. 

 

References

Chen, Y., Quan, S., Patil, V., Kunjamma, R.B., Tokars, H.M., Leisten, E.D., Chan, J., Wong, Y., & Popko, B. Insights into the mechanism of oligodendrocyte protection and remyelination by the integrated stress response. Glia, 71.  https://doi.org/10.1101/2023.01.23.525156

Voskuhl, R.R., Itoh, N., Tassoni, A., & Itoh, Y. Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A., 116. https://doi.org/10.1073/pnas.1821306116

1 comment:


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