Virtual Demyelination and Tight Junction Defect in PMP22 Deficiency (IN1-1.003)

Objective: This study is to test mechanisms compromising the safety factor of action potential propagation in PMP22 deficiency. Background Hereditary neuropathy with liability to pressure palsies (HNPP) is caused by heterozygous deletion of PMP22 . Our previous studies have shown that safety factor for action potential propagation in pmp22 +/- myelinated nerve fibers is impaired by excessive leakage of myelin. This study investigates whether defective assembly of tight junctions is responsible for the myelin leakage. Design/Methods: Pmp22+/- mice were examined by electrophysiology, histology, cell culture, and protein chemistry. Results: While Western blot showed normal levels of tight junction proteins, ZO1 and ZO2, immunohistochemistry demonstrated mis-localization of the two proteins in pmp22 +/- nerves. Because PMP22 is a constituent of inter-epithelial cell tight junctions, this cell model allows us to directly test whether PMP22 deficiency affects the function of the tight junctions. Epithelial cells were cultured after isolated from mouse renal tubules to the monolayer, the electrical resistances of the tight junctions were measured. There was a significant reduction of the resistance in both pmp22-/- (18.7±9.2; n=8 wells) and pmp22+/- mice (36.5±19.9; n=14 wells), compared with that in the wild-type mice (100.7±36.2; n = 14 wells; p Conclusions: Excessive myelin leakage develops in pmp22+/- myelin in the absence of demyelination, which is likely caused by abnormal assembly of tight junctions. This leakage would lead excessive outward current to shunt away depolarizing inward current and impair propagation of action potentials. Thus, this leakage is functionally similar to demyelination and we thus propose a novel pathogenic mechanism of 9virtual demyelination9. Supported by: NINDS R01NS066927-01. Disclosure: Dr. Guo has nothing to disclose. Dr. Yan has nothing to disclose. Dr. Sosinsky has nothing to disclose. Dr. Ellisman has nothing to disclose. Dr. Suter has nothing to disclose. Dr. Li has nothing to disclose.