CONDUCTION BLOCK IN HNPP

University Of California, San Diego, La Jolla CA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Conduction block (CB), a failure of action potential propagation along the nerve, causes neurological disabilities in a number of demyelinating diseases of the central and peripheral nervous systems, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multiple sclerosis. Disabilities from CB can be reversible, unlike disabilities in axonal degeneration, and should be particularly susceptible to rational therapies. The molecular basis for CB, however, is not well understood. Interestingly, patients with hereditary neuropathy with liability to pressure palsies (HNPP), an inherited condition with heterozygous deletion of chromosome 17p11.2 containing the PMP22 gene, are abnormally sensitive to mechanical force on the peripheral nerve, and develop reversible focal weakness and sensory loss which are probably due to CB. We are studying CB using an authentic animal model of HNPP, the pmp22 heterozygous knockout mouse (pmp22+/-). We found that CB can be mechanically induced more rapidly in the pmp22+/- mice than that in wild-type mice. We have identified frequent focal axonal constrictions encased by paranodal tomacula (excessive myelin folding), a pathological hallmark of HNPP. We hypothesize that the tomacula/axonal constrictions predispose the PMP22 deficient nerves to develop mechanically induced CB. Moreover, we have shown that inactivation of the p21-activated kinase type-1 (pak1) gene in PMP22 deficient mice eliminates tomacula/axonal constrictions, a novel signaling mechanism. We are interested in investigating the cellular and molecular basis for the development and recovery of CB, the formation of tomacula/axonal constrictions, and the therapeutic potential of PAK inhibitors. We aim to define the cellular and molecular factors that predispose pmp22+/- nerves to mechanically induced CB, and establish molecular signaling pathway for the formation of tomaculum/axonal constriction in the PMP22 deficiency. Results are expected to deepen our understanding on the molecular basis of CB, which may render insights into the pathogenesis for many demyelinating diseases.