Overall objectives: To characterize the molecular organization of lipids and proteins in myelin membranes; and to define the molecular interactions that stabilize the membrane packing in normal myelin and in myelin that has been modified by in vitro chemical treatment or by genetic or pathological conditions. A correlation of biophysical and biochemical techniques (including X-ray diffraction, electron microscopy, SDS-polyacrylamide gel electrophoresis, immunobloting, and thin-layer chromatography) applied to different types of specimens (including whole unfixed or fixed tissue, tissue homogenates, and reconstituted model systems of lipids and proteins) will be used to address the following specific questions: (1) Where are specific lipids and proteins localized in the myelin membrane? The effects of metal cations on the structure of intact myelin will be corrected with their binding to isolated myelin lipids and proteins and to reconstituted multi-layers of lipids and proteins. Changes in myelin composition of neurological mutant mice will be correlated with the structure of myelin membranes in these mutants. (2) What is the structural and chemical basis of the stability of membrane packing in myelin? Myelin fron neurological mutant mice will be surveyed for possible correlations between altered composition and changes in membrane packing. The chemical composition of the nerve sheaths from certain invertebrates and phylogenetically-older vertebrates will be related to the ultrastructure of the membrane assemblies in these sheaths. The dependence of membrane packing on lipid and protein composition will be determined from an analysis of multilayer structure in reconstituted model systems. (3) How do the specialized junctions in the myelin sheath relate to its stability? Attempts will be made to detail the organization and stability of paranodal axo-glial junctions by X-ray diffraction from unfixed nerve regions which are enriched in these structural differentiations of myelin. The meridional diffraction from central nervous system myelin will be analyzed with respect to its possible origins from the tight junctions peculiar to this myelin and from the organization of lipids and proteins in the plane of the myelin membrane.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS020824-03
Application #
3401456
Study Section
(SSS)
Project Start
1983-01-01
Project End
1989-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
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
Inouye, H (1994) X-ray scattering from a discrete helix with cumulative angular and translational disorders. Acta Crystallogr A 50 ( Pt 5):644-6

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