The PMP22 transgenic rat model represents a model for the most common human, hereditary peripheral neuropathy, Charcot-Marie-Tooth disease 1A. The CMT1A disease leads to a slowly progressing muscle weakness and sensitive symptoms in affected patients. Unfortunately, the pathomechanism of the disease has so far been poorly understood and no therapies are available for the patients. The CMT1A rat model reflects the characteristics of human diseases very well, and is therefore particularly suitable for researching the CMT1A disease both in basic scientific questions and with a view to the development of new therapeutic approaches. The CMT rat allows a better understanding of the cellular disease mechanism operating in human CMT1A, and should be helpful in the analysis of modifier genes, epigenetic factors, and in the evaluation of experimental treatment strategies. We also interest to investigate the motor unit-beyond Schwann cell pathology by examination the neuromuscular junctions (NMJ) and muscle pathology in CMT rats. Beyond established axonal and myelin deficits in CMT1A pathology, the impact of abnormal synaptic transmission at the neuromuscular junction (NMJ) has not been investigated in detail in preclinical trials. Structural and functional alterations of the NMJ are frequently present in affected nerves, but their contribution to impaired motor function remains unclear.
The dorsal root ganglion (DRG) co-culture system as an in vitro model for myelination represents the in vivo situation with close interaction between neurons, Schwann cells and fibroblasts. Different stages of the myelination process can be monitored (alignment of the Schwann cells with axons, early myelination and late myelination). The model allows easy the application of compounds via the medium to understand the metabolic pathways, cell signaling or protein-protein interaction. Also the Schwann cell culture system is established and allows an understanding of the mechanistically pathways of the myelination process and the cell signaling.
Beyond established axonal and myelin deficits in CMT1A pathology, the impact of abnormal synaptic transmission at the neuromuscular junction (NMJ) has not been investigated in detail in preclinical trials. Structural and functional alterations of the NMJ are frequently present in affected nerves, but their contribution to impaired motor function remains unclear. Previous investigations identified a reduced number of functional NMJs in a Pmp22 transgenic mouse model of CMT1A. In addition, synaptic dysfunction was shown to be a cause of muscle weakness and fatigue in a mouse model of CMT2D. Impaired synaptic transmission and the number and functionality of NMJs is thought to contribute to disease severity and progression in the Trembler-J mouse, a model of CMT1E carrying a mutation in the Pmp22 gene.