The Pathophysiology of Conduction Block in HNPP

Wayne State University, Detroit MI

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Abstract

DESCRIPTION (provided by applicant): Conduction block (CB) has been shown to be a major cause of neurological signs and symptoms in a number of acquired demyelinating diseases of the central and peripheral nervous systems, including Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN) and multiple sclerosis (MS). Interestingly, patients with hereditary neuropathy with liability to pressure palsy (HNPP), an inherited condition, are abnormally sensitive to mechanical compression of peripheral nerve, and commonly develop episodes of transient weakness and sensory loss that are probably due to CB. Disability from CB can be reversible, unlike disability in axonal degeneration, and should therefore be particularly susceptible to rational therapies. The molecular basis for CB, however, is not well understood. In this grant we have begun to study the molecular basis of CB in the peripheral nerve using an animal model of mechanical compression causing CB. Mechanical compression is a well known cause of CB in humans, and Gilliatt and colleagues have demonstrated that reversible CB correlates with clinical signs of weakness in an animal model. In this proposal we will investigate the cellular and molecular basis for the development and recovery of CB caused by mechanical compression both in wild type mice and in an animal model of HNPP in which one of the two pmp22 alleles has been inactivated by homologous recombination. Taken together these experiments will define the molecular abnormalities responsible for compression induced CB in myelinated nerve, and identify the factors that predispose pmp22 deficient nerves to develop CB. These studies will require the following Specific Aims: Aim 1: Test the hypothesis that compression induced CB is caused by obstructing access to voltage-gaited sodium channels at nodes of Ranvier and/or subsequent demyelination. Aim 2: Test the hypothesis that haplo-insufficiency of PMP22 predisposes development of CB and to identify the associated molecular abnormalities. Aim 3: Test the hypothesis that increasing age or multiple injuries predispose CB in pmp22 +/- and wild type mice.