Genomes and Genes
Axonal alterations in demyelinating diseases
Principal Investigator: STEVEN SIMON SCHERER
Abstract: 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 In unpublished work, we have found the alphas isoform of Na,K-ATPase is the only one that is clearly localized to axons, that it is (surprisingly) excluded from nodes, and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.
Funding Period: ----------------2002 - ---------------2011-
more information: NIH RePORT
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Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
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Department of Neuroscience, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104
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The University of Pennsylvania Medical School, Philadelphia, Pennsylvania
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Department of Neurology, University of Michigan, Ann Arbor, MI 48109 2200, USA
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Department of Genomics and Proteomics, Instituto de Biomedicina, CSIC, Valencia, Spain
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Department of Clinical Neurosciences, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, PA, USA
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Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
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Department Physiology and Neuroscience, NYU School of Medicine, New York, New York, USA
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Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA
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Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA
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Neuroscience Laboratory and Neurology Clinics, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
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Department of Neurology, University of Pennsylvania Medical Center, 3400 Spruce Street, 3W Gates Neurology, Philadelphia, Pennsylvania 19104, USA
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