The mannosidoses and ceroid-lipofuscinoses: Experimental studies on two types of storage disease

Abstract

alpha-Mannosidosis of Angus calves was studied both for its veterinary importance and as a model of analogous human lysosomal storage diseases. This study facilitated a similar study in Australia on Swainsona spp. intoxication of livestock in which the toxic principle was shown to be an indolizidine alkaloid, Swainsonine. These genetic and acquired alpha-mannosidoses are compared with beta-mannosidosis. Collectively the study has helped the understanding of the processes of glycosylation and catabolism of glycoproteins. An experiment of nature involving an alpha-mannosidosis chimeric calf born co-twin to a normal calf helped to define the expectations and limitations of bone marrow transplants in this type of storage disease in humans. The inherited ceroid-lipofuscinoses (Batten disease) were studied in an ovine model. Isolation and analyses of the fluorescent accumulated lipopigment denied the dogma of lipid peroxidation current in the 1970s and 1980s. It was shown that in this, and analogous diseases in humans, the dominantly accumulated species was the very hydrophobic protein, subunit c of mitochondrial ATP synthase. Contrary to the adage that this should reflect a disorder of lysosomal proteolysis, there is accumulating evidence that the primary defect resides in mitochondria. Because of its hydrophobic nature, subunit c forms paracrystaline complexes which appear resistant to proteolysis within the lysosomal apparatus.