Abstract

Overall objective: To characterize the molecular organization of lipids and proteins in nerve myelin membranes; and to define the molecular interaction that stabilize the membrane arrays. A correlation of biophysical and biochemical technique (including X-ray diffraction, electron microscopy, SDS polyacrylamide gel electrophoresis, immunoblotting, and thin-layer chromatography) applied to different types of specimens (including whole unfixed or fixed tissue, tissue homogenates, tissue fractions, and model systems of lipids and proteins) will be used to address the following specific questions (1) What is the fine-structure and composition of the interlamellar tight junctions of CNS myelin? Computer image analysis will be carried out on electron micrographs. SDS-PAGE/immunoblotting will be used to identify proteins in tissue fractions that are enriched in the junctions. X-ray patterns will be recorded from intact CNS myelin after contrast enhancement of the junctions, and also from tissue fractions enriched in the junctions. (2) What is the arrangement of lipids and proteins in myelin? Correlation between biochemical and X-ray measurements will be made for selected neuron logical mutants of the mouse, certain phylogenetically-older vertebrates, different nerves from within the peripheral nervous system, and isolated myelin preparations. Structural modifications of myelin induced by specific metal cations will be analyzed. The structure and inter-bilayer interaction of multilayers reconstituted from non-denatured proteolipids protein (PLP) plus myelin lipids, and PLP plus myelin basic protein will be analyzed. (3) What is the structural basis of demyelination? The structural and biochemical effects of calcium-ionophore and complement on CNS myelin will be determined. The integrity of interlamellar tight junctions will be examined in white matter from animals having experimental allergic encephalomyelitis and from autopsy material of humans with multiple sclerosis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020824-11
Application #
3401466
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1983-01-01
Project End
1995-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Kirschner, Daniel A; Karthigesan, Jothie; Bizzozero, Oscar A et al. (2008) Myelin structure and composition of myelinated tissue in the African lungfish. Neuron Glia Biol 4:59-70
Bond, J P; Kirschner, D A (1997) Spinal cord myelin is vulnerable to decompression. Mol Chem Neuropathol 30:273-88
Karthigasan, J; Garvey, J S; Ramamurthy, G V et al. (1996) Immunolocalization of 17 and 21.5 kDa MBP isoforms in compact myelin and radial component. J Neurocytol 25:1-7
Kirschner, D A; Szumowski, K; Gabreels-Festen, A A et al. (1996) Inherited demyelinating peripheral neuropathies: relating myelin packing abnormalities to P0 molecular defects. J Neurosci Res 46:502-8
Kirschner, D A; Inouye, H; Saavedra, R A (1996) Membrane adhesion in peripheral myelin: good and bad wraps with protein P0. Structure 4:1239-44
Karthigasan, J; Evans, E L; Vouyiouklis, D A et al. (1996) Effects of rumpshaker mutation on CNS myelin composition and structure. J Neurochem 66:338-45
Karthigasan, J; Inouye, H; Kirschner, D A (1995) Implications of the sequence similarities between tau and myelin basic protein. Med Hypotheses 45:235-40
Billings-Gagliardi, S; Kirschner, D A; Nadon, N L et al. (1995) Jimpy 4J: a new X-linked mouse mutation producing severe CNS hypomyelination. Dev Neurosci 17:300-10
Sedzik, J (1995) Regression analysis of factorially designed trials--a logical approach to protein crystallization. Biochim Biophys Acta 1251:177-85
Montag, D; Giese, K P; Bartsch, U et al. (1994) Mice deficient for the myelin-associated glycoprotein show subtle abnormalities in myelin. Neuron 13:229-46

Showing the most recent 10 out of 44 publications