We hypothesize that in normal myelinated PNS axons, the combination of Kv1.1, Kv1.2, KCNQ2, and KCNQ3 is necessary for repolarization, and that the misexpression of Kv3.1 b has a deleterious effect on axonal conduction of de/remyelinated axons. In unpublished work, we have found the alphas isoform of Na,K-ATPase is the only one that is clearly localized to axons, that it is (surprisingly) excluded from nodes, and appears to be focally diminished by demyelination. Thus, we also hypothesize that the misexpression of alphas may contribute to depolarization of de/remyelinated axons. The proposed experiments build on these findings, with the central theme of illuminating how K+ homeostasis works in normal and de/remyelinated axons.
Aim #1 : Do Kv3.1b channels contribute to conduction failure in demyelinating diseases? We will investigate whether KvS.lb is the 4-AP-sensitive channel by comparing the effects of DTX-I and 4- AP on axonal conduction in TremblerJ mice on a KvS.lb -null (Kcncl-/-) versus Kcnc1+/+ background.
Aim #2 : What is the role of KCNQ2 in myelinated axons? Because Kcnq2-null mice die at birth, before myelination and the formation of nodes, we will generate a conditional Kcnq2-null mouse and analyze the structure and function of myelinated axons, including the expression of KCNQ3.
Aim #3 : What Na,K-ATPase isoforms are expressed by myelinated axons and demyelinated axons? we will localize alpha1-3 by immunoelectron microscopy in CMSand PNS myelinated axons, along with their beta subunits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043174-09
Application #
8013782
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Gwinn, Katrina
Project Start
2002-04-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2011
Total Cost
$337,641
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Lancaster, Eric; Elman, Lauren B; Scherer, Steven S (2010) A patient with neurofibromatosis type 1 and Charcot-Marie-Tooth disease type 1B. Muscle Nerve 41:555-8
Vavlitou, Natalie; Sargiannidou, Irene; Markoullis, Kyriaki et al. (2010) Axonal pathology precedes demyelination in a mouse model of X-linked demyelinating/type I Charcot-Marie Tooth neuropathy. J Neuropathol Exp Neurol 69:945-58
Yum, Sabrina W; Zhang, Junxian; Mo, Katie et al. (2009) A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy. Ann Neurol 66:759-70
Devaux, Jerome; Gow, Alexander (2008) Tight junctions potentiate the insulative properties of small CNS myelinated axons. J Cell Biol 183:909-21
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