Gary Birnbaum, MD
Understanding ways to promote healing in MS
Updated: Jan 28, 2019
Lu G, Zhang M, Wang J, Zhang K, Wu S, Zhao X. Epigenetic regulation of myelination in health and disease. Eur J Neurosci. 2019.
a) Genes are essential for the production of proteins such as myelin. However, genes be blocked producing their proteins.
b) A variety of external factors can block gene function. The study of only those genes that are actually active is called “epigenetics.”
c) Loss of central nervous system myelin, the insulation around nerve cell projections (axons), is a major cause of disability in MS.
d) Prevention of myelin loss is a major treatment goal, as is inducing myelin repair. Unfortunately, no “remyelinating” therapies are currently available.
e) Cells called “oligodendrocytes” make myelin. Myelin production is tightly controlled to prevent aberrant myelin formation. As a result of such tight regulation myelin repair in the central nervous system is very limited.
f) Immature oligodendrocytes that have the capacity to mature and make myelin, are present in large numbers around areas of myelin loss in MS. They are prevented from becoming mature oligodendrocytes by a variety of myelin gene inhibitors.
g) The above paper presents a detailed summary of the multiple inhibitors of myelin gene expression present in the central nervous system, and how inhibition of the inhibitors promotes recovery from experimental demyelination.
h) The paper also discusses compounds that can reverse myelin gene inhibition and thus increase myelin production.
i) Understanding the regulation of myelin formation and the means to induce immature oligodendrocyte to mature and replace lost myelin is critical to finding an effective therapy for repair of MS lesions.
The paper cited above goes into great detail regarding what is known about the regulation of gene expression related to formation of myelin in both the central nervous system and the peripheral nervous system. It is beyond the purview of this blog to go into such detail (I promised not to put you into deep slumber with esoteric medical jargon), but what I found most interesting and exciting is that recent advances, cited in the paper, showed how modulation of myelin gene expression had a substantive effect in reducing disease severity in animal models of demyelination, and how a lack of myelin gene stimulatory factors are present at sites of MS demyelination. The therapeutic potential of increasing myelin production by enhancing OPC differentiation into oligodendrocytes is enormous. However, in that context, it is important to note that myelin can only form around intact axons. Since axonal loss occurs very early in MS, remyelinating therapies will need to be added to more standard, anti-inflammatory disease-modifying therapies to prevent axonal destruction. Given the costs of current disease-modifying therapies, the addition of another, most likely expensive drug as part of an “MS therapeutic cocktail,” could become problematic, but that is a discussion for another episode of this blog.
Myelin is lipid-rich structure that is necessary to avoid leakage of electric signals and to ensure saltatory impulse conduction along axons. Oligodendrocytes in central nervous system (CNS) and Schwann cells in peripheral nervous system (PNS) are responsible for myelin formation. Axonal demyelination after injury or diseases greatly impairs normal nervous system function. Therefore, understanding how the myelination process is programmed, coordinated, and maintained is crucial for developing therapeutic strategies for remyelination in the nervous system. Epigenetic mechanisms have been recognized as a fundamental contributor in this process. In recent years, histone modification, DNA modification, ATP-dependent chromatin remodeling, and non-coding RNA modulation are very active area of investigation. We will present a conceptual framework that integrates crucial epigenetic mechanisms with the regulation of oligodendrocyte and Schwann cell lineage progression during development and myelin degeneration in pathological conditions. It is anticipated that a refined understanding of the molecular basis of myelination will aid in the development of treatment strategies for debilitating disorders that involve demyelination, such as multiple sclerosis in the CNS and neuropathies in the PNS. This article is protected by copyright. All rights reserved.