Sterol and fatty acid synthesis in developing brains of three myelin-deficient mouse mutants

Abstract

1. 1. The rate of sterol synthesis and the level of hydroxymethylglutaryl-CoA (HMG-CoA) reductase were previously shown to be subnormal in the myelin-deficient brains of jimpy ( jp/Y) mutants. To determine whether these changes were specific for the jimpy mutation, rates of sterol synthesis and other aspects of lipid synthesis in jimpy brains were compared with those in the brains of two other mutants with defective myelination of the central nervous system, quaking ( qk/qk) and myelin synthesis deficiency ( msd/Y). 2. 2. The rate of sterol synthesis from [1- 14C]acetate or from [2- 14C]mevalonic acid and the level of HMG-CoA reductase were depressed in all three mutations at the earliest age at which clinical symptoms of the disorders were apparent. Ratios of cholesterol to desmosterol in developing brains of the three mutations were normal. 3. 3. The heat stability and the K m (HMG-CoA) of brain HMG-CoA reductase were not affected by the three mutations. 4. 4. The rate of fatty acid synthesis from [1- 14C]acetate was depressed in qk/qk brains but not in jp/Y or msd/Y brains. 5. 5. Rates of sterol, fatty acid, and CO 2 production in brain were not reduced in two neuromuscular mutants (reeler ( rl/rl) and oscillator ot/ot) with depressed growth rates but without known myelin deficiencies or in normal immature mice deprived of food, indicating that inadequate nutrition was not a cause for the observed deficiencies in lipid synthesis rates.