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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS048204-04
Application #
7324821
Study Section
NST-2 Subcommittee (NST)
Program Officer
Porter, John D
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
4
Fiscal Year
2008
Total Cost
$122,079
Indirect Cost
Name
Wayne State University
Department
Neurology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Bai, Yunhong; Zhang, Xuebao; Katona, Istvan et al. (2010) Conduction block in PMP22 deficiency. J Neurosci 30:600-8
Katona, Istvan; Wu, Xingyao; Feely, Shawna M E et al. (2009) PMP22 expression in dermal nerve myelin from patients with CMT1A. Brain 132:1734-40
Saporta, Mario A; Katona, Istvan; Lewis, Richard A et al. (2009) Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A. Brain 132:3263-73
Zhang, Xuebao; Chow, Clement Y; Sahenk, Zarife et al. (2008) Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain 131:1990-2001
Li, Jun (2008) Hypothesis of double polarization. J Neurol Sci 275:33-6
Kramer, Laura D; Li, Jun; Shi, Pei-Yong (2007) West Nile virus. Lancet Neurol 6:171-81
Li, Jun; Ghandour, Khaled; Radovanovic, Danijela et al. (2007) Stoichiometric alteration of PMP22 protein determines the phenotype of hereditary neuropathy with liability to pressure palsies. Arch Neurol 64:974-8
Li, Jun; Bai, Yunhong; Ianakova, Emilia et al. (2006) Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol 498:252-65
Bai, Yunhong; Ianokova, Emilia; Pu, Qin et al. (2006) Effect of an R69C mutation in the myelin protein zero gene on myelination and ion channel subtypes. Arch Neurol 63:1787-94
Shy, Michael E; Scavina, Mena T; Clark, Alisa et al. (2006) T118M PMP22 mutation causes partial loss of function and HNPP-like neuropathy. Ann Neurol 59:358-64

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