Newly Identified Deficiencies in the Multiple Sclerosis Central Nervous System and Their Impact on the Remyelination Failure

Abstract

The pathogenesis of multiple sclerosis (MS) remains enigmatic and controversial. Myelin sheaths in the central nervous system (CNS) insulate axons and allow saltatory nerve conduction. MS brings about the destruction of myelin sheaths and the myelin-producing oligodendrocytes (ODCs). The conundrum of remyelination failure is, therefore, crucial in MS. In this review, the roles of epidermal growth factor (EGF), normal prions, and cobalamin in CNS myelinogenesis are briefly summarized. Thereafter, some findings of other authors and ourselves on MS and MS-like models are recapitulated, because they have shown that: (a) EGF is significantly decreased in the CNS of living or deceased MS patients; (b) its repeated administration to mice in various MS-models prevents demyelination and inflammatory reaction; (c) as was the case for EGF, normal prion levels are decreased in the MS CNS, with a strong correspondence between liquid and tissue levels; and (d) MS cobalamin levels are increased in the cerebrospinal fluid, but decreased in the spinal cord. In fact, no remyelination can occur in MS if these molecules (essential for any form of CNS myelination) are lacking. Lastly, other non-immunological MS abnormalities are reviewed. Together, these results have led to a critical reassessment of MS pathogenesis, partly because EGF has little or no role in immunology.

Keywords: cobalamin; epidermal growth factor; multiple sclerosis; multiple sclerosis pathogenesis; normal cellular prions; remyelination failure.

Figure 1

The main effects of epidermal growth factor (EGF) on oligodendrocytes (ODCs) and astrocytes (ASTs). The green arrows indicate stimulation. See text for details and references. IGF = insulin-like growth factor; NSC = neural stem cell; OPC = oligodendrocyte precursor cell; PrP^C = normal cellular prion protein.

Figure 2

Various physiological molecules of the central nervous system (CNS) act through the Akt signaling pathway. The pivotal role of the Akt signaling pathway in CNS myelination is evident. See text for details and references. Cbl = cobalamin; ECM = extracellular matrix; EGF = epidermal growth factor; IGF = insulin-like growth factor; mTORC = mammalian target of rapamycin complex; NRG = neuregulin; ODC = oligodendrocyte; PrP^C = normal cellular prion protein.

Figure 3

Schematic diagram of the epidermal growth factor (EGF) levels in multiple sclerosis (MS) central nervous system (CNS), EGF expression, and the effects of its in vivo or in vitro administration in different models of experimental allergic encephalomyelitis (EAE) and chemically or virally-induces CNS demyelination. See the text for details and references. CSF = cerebrospinal fluid; MPG = myelin oligodendrocyte-specific glycoprotein.