Abstract
Cholesterol in the mammalian brain is a risk factor for certain neurodegenerative diseases, raising the question of its normal function. In the mature brain, the highest cholesterol content is found in myelin. We therefore created mice that lack the ability to synthesize cholesterol in myelin-forming oligodendrocytes. Mutant oligodendrocytes survived, but CNS myelination was severely perturbed, and mutant mice showed ataxia and tremor. CNS myelination continued at a reduced rate for many months, and during this period, the cholesterol-deficient oligodendrocytes actively enriched cholesterol and assembled myelin with >70% of the cholesterol content of wild-type myelin. This shows that cholesterol is an indispensable component of myelin membranes and that cholesterol availability in oligodendrocytes is a rate-limiting factor for brain maturation.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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2',3'-Cyclic-Nucleotide Phosphodiesterases / metabolism
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Age Factors
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Animals
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Animals, Newborn
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Apolipoproteins E / metabolism
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Behavior, Animal
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Blotting, Northern / methods
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Blotting, Southern / methods
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Blotting, Western / methods
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Cell Membrane / metabolism
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Central Nervous System / metabolism
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Cholesterol / deficiency
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Cholesterol / physiology*
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Chromatography, Thin Layer / methods
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Cloning, Molecular
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Creatine / metabolism
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Farnesyl-Diphosphate Farnesyltransferase / deficiency
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Farnesyl-Diphosphate Farnesyltransferase / genetics
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Farnesyl-Diphosphate Farnesyltransferase / metabolism
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Gene Expression Regulation, Developmental / physiology*
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In Situ Hybridization / methods
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Lipid Metabolism
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Mass Spectrometry / methods
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Mice
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Mice, Inbred C57BL
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Mice, Mutant Strains / physiology
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Microscopy, Electron, Transmission / methods
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Microsomes / metabolism
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Myelin Proteolipid Protein / metabolism
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Myelin Sheath / metabolism*
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Myelin Sheath / ultrastructure
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Oligodendroglia / metabolism*
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Oligodendroglia / ultrastructure
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Phenotype
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Psychomotor Performance / physiology
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RNA / analysis
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Receptors, LDL / metabolism
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Silver Staining / methods
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Spinal Cord / metabolism
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Spinal Cord / ultrastructure
Substances
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Apolipoproteins E
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Myelin Proteolipid Protein
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Receptors, LDL
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RNA
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Cholesterol
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Farnesyl-Diphosphate Farnesyltransferase
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2',3'-Cyclic-Nucleotide Phosphodiesterases
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Creatine