CHANGES IN THE LEVELS OF DOLICHOL AND DOLICHYL-PHOSPHATE IN A MURINE MODEL OF NIEMANN-PICKS TYPE-C DISEASE

The distributions of mevalonate pathway lipids in various organs of a mouse strain used as a model for Niemann-Pick's type C disease were an alyzed. Extensive accumulation of cholesterol was observed in all tiss ues with the exception of the brain, where the content of this lipid w as decreased. The changes in total dolichol contents of most organs va ried from a 50% decrease in the lung to a twofold increase in kidney a nd heart. There was relative enrichment of longer-chain dolichols, but no increase in the relative amount of alpha-unsaturated polyprenols w as observed, The levels of dolichyl phosphate in all organs were incre ased, and most of this lipid was associated with bound oligosaccharide s or proteins, Ubiquinone levels were largely unchanged. Subfractionat ion studies revealed that heavy and light lysosomes exhibited a 10-fol d increase in cholesterol level, the amount of dolichol was decreased in lysosomes and increased in microsomes, and there was an increase in the dolichyl phosphate levels of ail three of these subfractions, The se results indicate that in diseased mice cholesterol accumulation in various organs is paralleled by an increase in the dolichyl phosphate concentration, whereas dolichol transport from the endoplasmic reticul um to lysosomes is inhibited.