Schwann cell differentiation in Charcot-Marie-Tooth disease 1 A (CMT1A)

Abstract

Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peripheral myelin protein 22 gene (PMP22) causes the most frequent sub-form Charcot-Marie-Tooth 1A (CMT1A). In contrary to the notion that CMT1A manifests in the second decade of life, moderate walking disability and electrophysiological abnormalities are usually already present during childhood. The early onset and developmental nature of the disease is also supported by findings derived from a Pmp22 transgenic rat model for CMT1A (CMT rat), which displays a reduced number of myelinated fibers per peripheral nerve already early postnatally and never reaches a wildtype level throughout development. RNA transcription analysis has revealed that there is a striking continuous upregulation of Schwan cell neuregulin 1 type I (NRG1_I) which we could show that it is contributing to the reported hypermyelination of small caliber axons in CMT1A rodent models. On the other hand, CMT rat Schwann cells show a strongly impaired lipid biogenesis required for myelination as assessed by RNA expression and lipid profiling of peripheral nerve transcriptomes and myelin composition, respectively. Importantly, Pmp22 overexpressing Schwann cell also reflects an impaired myelination competence in vitro, when co-cultured with dorsal root ganglia neurons. A remarkable improvement of Schwann cell myelination upon supplementation with phosphatidylcholine in vitro has led to the hypothesis that exogenous supplementation with lipids in vivo may improve disease progression. Indeed, we observed improved disease progression on the histological, electrophysiological and behavioral levels in CMT rats which were fed with a chow enriched in lecithin from P2 to adulthood. Moreover, disease amelioration is also visible after late long term (P21-P112) and early short term treatment (P2 to P21), but the effect is fading after treatment cessation. Therefore, continuously supplying patients with exogenous lipids may be considered as a promising therapeutic approach for CMT1A disease. Figure 1:The Schwann cell developmental lineage and repair response. The diagram shows the main developmental cell types, repair (Bungner) Schwann cell and steps of Schwann cell development. Solid arrows indicate developmental steps. Red arrows indicate Schwann cell injury associated transformation into repair cell. Dashed arrows indicate post-repair response. E stands for embryonic time points in mouse development. (Adapted from K. R. Jessen and R. Mirsky (2016).Figure 2:Schematic structures of major NRG1 isoforms in the nervous system. Unlike type III isoform, has two transmembrane domains, other isoforms (I&II) have only one transmembrane domain. Proteolytic cleavage in the juxta-membrane area releases the epidermal growth factor (EGF) domain containing part of both I&II isoforms while III remain anchored to the membrane. Adaptaed from Jessen & Mirsky 2005.