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.
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We dedicate this work to P. Morell for his pioneering work on brain cholesterol synthesis. We thank L. Bitterberg, A. Fahrenholz, S. Keese, I. Leibrecht, E. Nicksch and M. Schindler for excellent technical help; M. Schwab for providing us with antibodies; and M. Simons for helpful comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (SFB523 to K.A.N.; Wi654/7 to B.B. and F.W.), the Hertie Institute of Multiple Sclerosis Research and grants from the European Union (K.A.N.).
The authors declare no competing financial interests.
Loss of SQS in mutant primary oligodendrocytes. (PDF 51 kb)
Measurement of cholesterol in myelin. (PDF 26 kb)
Reduction of myelin mRNAs during postnatal development. (PDF 10 kb)
Astroglial cells as candidates to provide cholesterol. (PDF 73 kb)
No 'rescue' by cholesterol-rich diet. (PDF 54 kb)
Lipid content in purified myelin. (PDF 9 kb)
Mutants at 20 days of age show strong tremors and ataxia. (MOV 1104 kb)
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