High cholesterol level is essential for myelin membrane growth.
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.
Saher
Gesine
G
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Goettingen, Germany.
Brügger
Britta
B
Lappe-Siefke
Corinna
C
Möbius
Wiebke
W
Tozawa
Ryu-ichi
R
Wehr
Michael C
MC
Wieland
Felix
F
Ishibashi
Shun
S
Nave
Klaus-Armin
KA
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000378:metabolism; D001522:Behavior, Animal; D015152:Blotting, Northern / Q000379:methods; D015139:Blotting, Southern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D002784:Cholesterol / Q000172:deficiency / Q000502:physiology*; D002855:Chromatography, Thin Layer / Q000379:methods; D003001:Cloning, Molecular; D003401:Creatine / Q000378:metabolism; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D017403:In Situ Hybridization / Q000379:methods; D050356:Lipid Metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000502:physiology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008861:Microsomes / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology; D012313:RNA / Q000032:analysis; D011973:Receptors, LDL / Q000378:metabolism; D016622:Silver Staining / Q000379:methods; D013116:Spinal Cord / Q000378:metabolism / Q000648:ultrastructure
D001057:Apolipoproteins E; D018991:Myelin Proteolipid Protein; D011973:Receptors, LDL; D012313:RNA; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D003401:Creatine