Peroxisomal Impairment in Niemann-Pick Type C Disease

Abstract

Niemann-Pick type C disease (NPC) belongs to the group of lysosomal storage diseases characterized by an accumulation of cholesterol and sphingomyelin. Using a mutant mouse strain, enzymatic markers for lysosomes, mitochondria, microsomes, and peroxisomes were investigated in the liver and brain. Aside from lysosomal changes, we found a sizable decrease of peroxisomal beta-oxidation of fatty acids and catalase activity in the brain and liver. Isolated peroxisomes displayed a significant decrease of these enzyme activities. Furthermore, the only phospholipid change in brain was a decreased content of the plasmalogen form of phosphatidylethanolamine, and the dimethylacetal pattern was also modified. The electron microscopical appearance of peroxisomes did not display any large changes. The defect of peroxisomal enzymes was already present 18 days before the onset of the disease. In contrast, the lysosomal marker enzyme increased in activity only 6 days after appearance of the symptoms. The events of the studied process have previously been considered to be elicited by a lysosomal deficiency, but this study demonstrates disturbances similar to those in a number of peroxisomal diseases. It appears that the peroxisomal impairment is an early event in the process and could be a factor in the development of Niemann-Pick type C disease.