1. The 'CMT Rat': Peripheral Neuropathy and Dysmyelination Caused by Transgenic Overexpression of PMP22
- Author
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Ueli Suter, Moritz J. Rossner, Stephan Niemann, Hans-Michael Meinck, Helen Stewart, Klaus-Armin Nave, Michael W. Sereda, and Ian R. Griffiths
- Subjects
General Neuroscience ,Transgene ,Schwann cell ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Myelin assembly ,Muscle hypertrophy ,Cell biology ,Cell membrane ,Myelin ,medicine.anatomical_structure ,Peripheral neuropathy ,nervous system ,History and Philosophy of Science ,medicine ,Neuroscience ,Intracellular - Abstract
We have generated a transgenic rat model of Charcot-Marie-Tooth disease type 1A (CMT1A) providing formal proof that this neuropathy can be caused by increased expression of peripheral myelin protein-22 (PMP22). Heterozygous PMP22-transgenic rats develop muscle weakness and gait abnormalities as well as reduced nerve conduction velocities and EMG abnormalities, which closely resemble recordings in patients with CMT1A. Dys- and demyelination, Schwann cell hypertrophy, and "onion bulb" formation are also similar to findings in humans. When bred to homozygosity, transgenic rats completely fail to elaborate myelin, but all myelin-forming Schwann cells segregate with axons in the normal one-to-one ratio. Although arrested at this "promyelin" stage, differentiation proceeds in homozygous rats at the molecular level, as demonstrated by high-level expression of myelin structural genes. Intracellular trafficking of the wild-type protein is not visibly impaired, even when strongly overexpressed, suggesting that PMP22 blocks myelin assembly in a late Golgi/cell membrane compartment of the affected Schwann cell.
- Published
- 2017