Neural and molecular features on Charcot-Marie-Tooth disease plasticity and therapy

Abstract

In the peripheral nervous system disorders plasticity is related to changes on the axon and Schwann cell biology, and the synaptic formations and connections, which could be also a focus for therapeutic research. Charcot-Marie-Tooth disease (CMT) represents a large group of inherited peripheral neuropathies that involve mainly both motor and sensory nerves and induce muscular atrophy and weakness. Genetic analysis has identified several pathways and molecular mechanisms involving myelin structure and proper nerve myelination, transcriptional regulation, protein turnover, vesicle trafficking, axonal transport and mitochondrial dynamics. These pathogenic mechanisms affect the continuous signaling and dialogue between the Schwann cell and the axon, having as final result the loss of myelin and nerve maintenance; however, some late onset axonal CMT neuropathies are a consequence of Schwann cell specific changes not affecting myelin. Comprehension of molecular pathways involved in Schwann cell-axonal interactions is likely not only to increase the understanding of nerve biology but also to identify the molecular targets and cell pathways to design novel therapeutic approaches for inherited neuropathies but also for most common peripheral neuropathies. These approaches should improve the plasticity of the synaptic connections at the neuromuscular junction and regenerate cell viability based on improving myelin and axon interaction.

Figure 1

Peripheral nerve structure and cell localization of some CMT proteins at either the Schwann cell and myelin or the neuronal axon. (a) PMP22 and P0 are structural proteins located at the compact myelin and Cx32 at the noncompact myelin in the paranode (and also at the Schmidt-Lanterman incisures). Some other demyelinating CMT-associated molecules are SHT3TC2 at the plasmatic membrane and related to early endosomes and endosome recycling, the transcription factor ERG2 working in early promyelination programme, and NDRG1 that is ubiquitously expressed and has been proposed to play a role in growth arrest and cell differentiation, possibly as a signaling protein shuttling between the cytoplasm and the nucleus. Proteins mainly related to axonal CMT are associated with neurofilaments (NEFL), late endosomes (RAB7), mitochondria, endoplasmic reticulum and microtubules (MFN2 and GDAP1), or intermediate filaments (HSP22 and HSP27). (b) A ray sign indicates the main location where drugs or advanced therapies are acting. Stem cell therapy is represented as an open shadow grasping the neuron soma and axon and the Schwann cell. Trophic factors may be delivered as a drug but also by means of gene vectors or as a part of the local function of therapeutic stem cells. This figure was produced using Servier Medical Art (http://www.servier.com/servier-medical-art/powerpoint-image-bank).