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High cholesterol level is essential for myelin membrane growth

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.

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Figure 1: Inactivation of the squalene synthase gene (Fdft1) in oligodendrocytes.
Figure 2: Clinical phenotype.
Figure 3: Hypomyelination of CNS white matter tracks.
Figure 4: Ultrastructure of oligodendrocytes and myelin.
Figure 5: Biochemistry of mutant myelin.
Figure 6: Lipid analysis and detergent-resistant membranes.
Figure 7: Natural compensation for cholesterol deficiency.

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Acknowledgements

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.).

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Correspondence to Klaus-Armin Nave.

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Supplementary information

Supplementary Fig. 1

Loss of SQS in mutant primary oligodendrocytes. (PDF 51 kb)

Supplementary Fig. 2

Measurement of cholesterol in myelin. (PDF 26 kb)

Supplementary Fig. 3

Reduction of myelin mRNAs during postnatal development. (PDF 10 kb)

Supplementary Fig. 4

Astroglial cells as candidates to provide cholesterol. (PDF 73 kb)

Supplementary Fig. 5

No 'rescue' by cholesterol-rich diet. (PDF 54 kb)

Supplementary Table 1

Lipid content in purified myelin. (PDF 9 kb)

Supplementary Video 1

Mutants at 20 days of age show strong tremors and ataxia. (MOV 1104 kb)

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Saher, G., Brügger, B., Lappe-Siefke, C. et al. High cholesterol level is essential for myelin membrane growth. Nat Neurosci 8, 468–475 (2005). https://doi.org/10.1038/nn1426

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