Role of lipid interactions in autoimmune demyelination.
A morphological transformation involving loss of adhesion between myelin lamellae and formation of myelin vesicles has been described as a mechanism for demyelination in multiple sclerosis and marmoset experimental allergic encephalomyelitis (EAE). Although protein interactions are involved in maintaining normal myelin structure, we describe here how lipids contribute to myelin stability and how lipid changes in EAE, including increases in lipid polyunsaturation and negatively charged phosphatidylserine (PS), promote demyelination. Three physico-chemical techniques were used to identify these changes: (1) Langmuir monolayer isotherms indicated that EAE white matter lipids were significantly more "expanded" (fluid) than controls. (2) NMR spectroscopy indicated that EAE myelin lipids were more polyunsaturated than controls. (3) High-performance liquid chromatography (HPLC) with an evaporative light scattering detector indicated increased PS in EAE compared to controls, while sphingomyelin (SM), sulfatides and phosphatidylcholine (PC) were decreased. We present a physical model considering electrostatic, van der Waals and undulation forces to quantify the effect of these changes on myelin adhesion at the extracellular interface. Taken together, the isotherm, NMR, HPLC and modeling results support a mechanism for autoimmune demyelination whereby the composition of myelin lipids is altered in a manner that increases myelin fluidity, decreases myelin adhesion, increases membrane curvature, and promotes vesiculation.
Ohler
Benjamin
B
Center for the Study of Neurodegenerative Disorders, Neuroscience Research Institute, Biological Sciences 2, University of California, Santa Barbara, CA 93106-5060, USA.
Graf
Karlheinz
K
Bragg
Richard
R
Lemons
Travis
T
Coe
Robert
R
Genain
Claude
C
Israelachvili
Jacob
J
Husted
Cynthia
C
D000818:Animals; D015551:Autoimmunity; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002144:Callithrix; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008560:Membrane Fluidity; D008563:Membrane Lipids / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure
D008051:Lipid Bilayers; D008563:Membrane Lipids