Lipids of developing brain of twitcher mouse. An authentic murine model of human Krabbe disease.
Brains of the newly discovered neurological mutant of the mouse, twitcher, were analysed from birth to the terminal stage of the disease for major tissue constituents and the lipid composition. A genetic deficiency of galactosylceramidase is the underlying cause of this mutant. The affected mice failed to gain body weight after 20 days (30 per cent of normal at 42 days) but the brain weight was much less affected (85 per cent of normal at 42 days). The water content and the four major fractions, chloroform-methanol insoluble residue, chloroform-methanol soluble protein, upper phase solids and total lipid, were essentially unaltered except that the total lipid was reduced slightly towards the terminal stage. Among lipids, only galactolipids, galactosylceramide and sulphatide were abnormal in the twitcher brain. Galactosylceramide was decreased at 37 and 42 days whereas decrease in sulphatide occurred earlier from 25 days, resulting in an increased ratio of galactosylceramide to sulphatide. The analytical abnormalities found in the twitcher brain are qualitatively similar to and quantitatively milder than those in the brain of human patients with globoid cell leukodystrophy (Krabbe disease), of which the twitcher is an enzymatically authentic animal model. The secondary abnormalities observed in brains of human patients as the result of tissue devastation were generally not present in the twitcher brain. Mouse brains contain relatively little myelin. As the pathology in twitcher is greatest in the spinal cord and brainstem (Duchen et al., 1980), the fact that the changes in twitcher brains are quantitatively milder than those of human patients may partly reflect the relative amount of myelin in the two species. While more detailed studies of some specific constituents, such as galactosylsphingosine, and of other tissues, such as the peripheral nervous system and the kidney, will have to be performed, the present results serve as the reference for comparison between the human and murine galactosylceramidase deficiency states and for future experiments with the twitcher mutant, which is an invaluable tool for studies of globoid cell leukodystrophy.
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D004195:Disease Models, Animal; D007965:Leukodystrophy, Globoid Cell / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D008817:Mice, Mutant Strains