Molecular mechanisms of inherited demyelinating neuropathies

Abstract

The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies.

Fig. 1

Heterogeneous pathogenesis represents a challenge for developing unifying treatment strategies. This is a schematic representation of a myelinated axon, and the variety of subcellular locations that have been implicated as sites where mutant proteins disrupt myelination. The color code represents hypothetical grouping of genes by pathogenetic alteration. Red, protein quality control; brown, transcription; violet, gap junctions; green, membrane homeostasis; blue, extracellular matrix interactions; black, stability of compact myelin. The inset depicts the major pathways for the synthesis and degradation of intrinsic membrane proteins. Agg, aggresome; EE, early endosome, ER, endoplasmic reticulum; LE, late endosome; Lys, lysosome; Nuc, nucleus; Prot, proteasome.