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Review
. 2014 Mar 12:4:49-63.
doi: 10.2147/DNND.S54391. eCollection 2014.

Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms

Michael C Levin  1   2 , Joshua N Douglas  1   2 , Lindsay Meyers  1 , Sangmin Lee  1   3 , Yoojin Shin  1   3 , Lidia A Gardner  1   3
Affiliations
Review

Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms

Michael C Levin et al. Degener Neurol Neuromuscul Dis. .

Abstract

Multiple sclerosis (MS) is a complex autoimmune disease that impairs the central nervous system (CNS). The neurological disability and clinical course of the disease is highly variable and unpredictable from one patient to another. The cause of MS is still unknown, but it is thought to occur in genetically susceptible individuals who develop disease due to a nongenetic trigger, such as altered metabolism, a virus, or other environmental factors. MS patients develop progressive, irreversible, neurological disability associated with neuronal and axonal damage, collectively known as neurodegeneration. Neurodegeneration was traditionally considered as a secondary phenomenon to inflammation and demyelination. However, recent data indicate that neurodegeneration develops along with inflammation and demyelination. Thus, MS is increasingly recognized as a neurodegenerative disease triggered by an inflammatory attack of the CNS. While both inflammation and demyelination are well described and understood cellular processes, neurodegeneration might be defined by a diverse pool of any of the following: neuronal cell death, apoptosis, necrosis, and virtual hypoxia. In this review, we present multiple theories and supporting evidence that identify common biological processes that contribute to neurodegeneration in MS.

Keywords: autoantibodies; hypoxia; lipid and one-carbon metabolism; nuclear receptors; oxidative stress.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Schematic representation of the neurodegeneration theories. Note: Arrows represent increase (upward) and decrease (downward) in cellular processes and metabolites. Abbreviations: ATP, adenosine triphosphate; B6, vitamin B6; B12, vitamin B12; DNA, deoxyribonucleic acid; Hcy, homocysteine; HDL, high-density lipoprotein; ROS, reactive oxygen species.
Figure 2
Figure 2
Diagram of the one-carbon cycle. Notes: The major metabolites are presented in the blue frames (methionine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine); enzymes and cofactors are highlighted in the pink rectangles. Abbreviations: ATP, adenosine triphosphate; B6, vitamin B6; B12, vitamin B12; BHMT, betaine-homocysteine-S-methyl transferase; CBS, cystathionine beta synthase; DNA, deoxyribonucleic acid; GNMT, glycine N-methyltransferase; Hcy, homocysteine; MAT, methionine adenosyltransferase; MetRS, methionine-tRNA ligase; MS, methionine synthase; MT, methyl transferase; MTHFR, methylenetetrahydrofolate reductase; RNA, ribonucleic acid; SAHH, S-adenosylhomocysteine hydrolase.
Figure 3
Figure 3
PPARs regulation of cellular processes. Note: PPARs form complexes with RXR to control multiple cellular processes. Abbreviations: PPAR, peroxisome proliferator-activated receptor; RXR, retinoid X-receptor.
Figure 4
Figure 4
Common pathways of neurodegeneration. Note: Metabolic disturbances affect major regulators of cellular processes. Abbreviations: HIF, hypoxia inducible factor; NF-kβ, nuclear factor kappa β; PPARs, peroxisome proliferator-activated receptors; ROS, reactive oxygen species.
See this image and copyright information in PMC

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