Multiple Sclerosis

 

According to the W.H.O. nearly 2.8 million people around the world are affected by Multiple Sclerosis (MS). MS is an autoimmune, neurodegenerative disease that attacks the Central Nervous System (CNS). The pathology for this disease involves demyelination, inflammation, and axonal damage and or loss, followed by a remyelination/repair state that does not return the axons to their original function. Oligodendrocytes are glial cells found within the CNS that myelinate the axons of neurons. Myelin sheath is crucial for quick and speedy signal propagation down the axon. Demyelination refers to the destruction of the myelin sheath, axon insulator, and the degradation of transduction signals, meaning cells are unable to communicate effectively. Alongside this destruction, cellular debris accumulates in the surrounding environment, often resulting in apoptosis on the adjacent cells. Inflammation occurs as a result of T cell and B cell infiltration into the CNS after the Blood Brain Barrier permeabilizes. As these cells begin to attack the myelin sheath, Oligodendrocytes are overstressed, again resulting in further apoptosis, and a reduced ability for remyelination within the brain and spinal cord. Macrophages are also important cells throughout MS progression, contributing to tissue damage and producing reactive oxygen species and chemokines. High levels of macrophages are related to large amounts of demyelination, as they are directly involved in axonal damage. This all leads to cognitive impairments, with common symptoms of patients with MS including, but not limited to walking and coordination impairments, tremor, ataxia, and sensory problems. Most therapeutic options currently for MS patients consist of immunosuppressive medications; usually through B-cell depletion. However, these methods do not stop the disease progression and leave the patient’s body essentially unable to defend itself against infections and viruses because of the immune compensatory behavior of these medications. It’s important for researchers to implore possible cytoprotective therapies for the CNS in order to combat this horrible disease.

In the article titled, “m6A mRNA methylation is essential for oligodendrocyte maturation and CNS myelination,” postdoctoral researcher Vaibhav Patel discusses the importance of N6-methyladenosine (m6A) on the progression of Oligodendrocyte precursor cells (OPc’s) to mature oligodendrocytes (OL’s). They looked at the effects of inactivating the Mettl14 gene, which plays a role in the m6A methyltransferase complex and has been shown, when disrupted, to decrease neurogenesis. They hypothesize these  negative effects may be due to a decrease in m6A. They discovered that through the conditional knockout of the Mettl14 gene, that in vivo “myelin abnormalities and altered oligodendrocyte numbers.” When they later looked at in vitro, OPCs lacking Mettl14 did not properly differentiate into mature oligodendrocytes. Along with the effects the Mettl14 gene deletion had on m6a, they also discovered that, NF155, which is critical to the formation of a paranode, the myelin that surrounds the node, is differentially spliced and disrupted during myelination. Because of this, it’s hypothesized that epigenetic regulation of Mettl14 may be helpful in understanding more about the progression of MS. 

Because of this paper, and similar papers, research into possible gene’s important to myelination have been looked at in the terms of MS. The article titled, “A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis,” looks to implore the genetic risk factors and possible genetic upregulation in MS. Specifically, this paper explores the interplay between genetic risk factors and epigenetic regulation in multiple sclerosis (MS). Using a network model, it integrates GWAS data, DNA methylation profiles, and the human interactome to reconstruct an MS-associated gene regulatory network (GRN). Key findings include GWAS-mQTL colocalizations and enriched cell-type-specific signals in T follicular helper cells. The study identifies potential drug candidates, such as vorinostat and sivelestat, for MS treatment. Like stated before, it’s important to learn more about the disease; whatever front that may be, in order to hypothesize treatment options or further topics to research, something both of these papers seemed to play off of. Genetic regulation has been a key at looking at these demyelinating disorders, whether it be through regulation of transcription factors, or pharmacological activation somewhere in the pathway, this paper, I know, will open doors to further research down the route. 

References.  

World Health Organization. “Multiple Sclerosis.” Www.who.int, World Health Organization, 2023, www.who.int/news-room/fact-sheets/detail/multiple-sclerosis. 

Manuel, Astrid M et al. “A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis.” Human molecular genetics vol. 32,6 (2023): 998-1009. doi:10.1093/hmg/ddac265 

Xu, Huan et al. “m6A mRNA Methylation Is Essential for Oligodendrocyte Maturation and CNS Myelination.” Neuronvol. 105,2 (2020): 293-309.e5. doi:10.1016/j.neuron.2019.12.013