Multiple sclerosis: lessons from molecular neuropathology

Exp Neurol. 2014 Dec;262 Pt A:2-7. doi: 10.1016/j.expneurol.2013.12.003. Epub 2013 Dec 14.

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, which leads to widespread focal lesions of primary demyelination with variable axonal, neuronal and astroglia injury. The mechanisms responsible for tissue injury in the MS brain and spinal cord are only incompletely understood. In this review we discuss that the formation of confluent subpial cortical lesions is the most specific type of tissue damage, which is exclusively present in MS patients. Current data suggest that subpial demyelination is triggered by a soluble factor, which is produced in meningeal inflammatory infiltrates and diffuses into the cortical parenchyma, where it destroys myelin either directly or indirectly through microglia activation. The presence of demyelinating activity in sera and cerebrospinal fluid of MS patients is known for decades, but the molecular nature of the possibly underlying demyelinating factor is still unclear. Destruction of myelin sheaths and oligodendrocytes as well as neurodegeneration in MS are associated with massive oxidative stress and mitochondrial injury. Oxidative stress appears to be driven in early MS by activated microglia and oxidative burst and is, in the progressive stage of the disease, amplified by additional factors related to the age of patients and accumulation of pre-existing brain damage. Thus, the demyelinating factor in MS patients may either be a currently unknown cytokine or an inflammatory mediator or, alternatively, a mixture of cytokines. It may activate microglia towards uncontrolled oxygen radical production. Alternatively, the demyelinating factor may by itself trigger demyelination, which is then amplified by oxidative injury. The molecular characterization of the demyelinating factor may provide an important clue for the understanding of MS pathogenesis in the future.

Keywords: Demyelination; Multiple sclerosis; Neurodegeneration.

Publication types

  • Review

MeSH terms

  • Central Nervous System / pathology*
  • Humans
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / pathology*
  • Multiple Sclerosis / physiopathology