Myelin changes in Alexander disease

Neurologia. 2018 Oct;33(8):526-533. doi: 10.1016/j.nrl.2017.01.019. Epub 2017 Mar 22.
[Article in English, Spanish]

Abstract

Introduction: Alexander disease (AxD) is a type of leukodystrophy. Its pathological basis, along with myelin loss, is the appearance of Rosenthal bodies, which are cytoplasmic inclusions in astrocytes. Mutations in the gene coding for GFAP have been identified as a genetic basis for AxD. However, the mechanism by which these variants produce the disease is not understood.

Development: The most widespread hypothesis is that AxD develops when a gain of function mutation causes an increase in GFAP. However, this mechanism does not explain myelin loss, given that experimental models in which GFAP expression is normal or mutated do not exhibit myelin disorders. This review analyses other possibilities that may explain this alteration, such as epigenetic or inflammatory alterations, presence of NG2 (+) - GFAP (+) cells, or post-translational modifications in GFAP that are unrelated to increased expression.

Conclusions: The different hypotheses analysed here may explain the myelin alteration affecting these patients, and multiple mechanisms may coexist. These theories raise the possibility of designing therapies based on these mechanisms.

Keywords: Alexander disease; Astrocitos; Astrocytes; Chondroitin sulfate proteoglycan-NG2; Condroitín sulfato proteoglicano-NG2; Enfermedad de Alexander; Epigenetics; Epigenética; Glial fibrilar acidic protein; Mielinización; Myelination; Proteína acidica fibrilar glial.

Publication types

  • Review

MeSH terms

  • Alexander Disease / metabolism*
  • Alexander Disease / pathology
  • Animals
  • Glial Fibrillary Acidic Protein / metabolism
  • Humans
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology

Substances

  • Glial Fibrillary Acidic Protein