ANALYSIS OF CHOLESTEROL AND OXYSTEROL LEVELS IN NIEMANN PICK DISEASE TYPE C MICE AND PATIENTS

Objectives: Niemann Pick Disease Type C (NP-C) is a rare neurodegenerative condition affecting infants, children and adults. The majority of patients have NPC1 mutations, resulting and cholesterol esterification and trafficking defects. 95% of brain cholesterol is synthesized in situ and this is converted to oxysterols by direct oxidation or by action of oxysterol biosynthetic enzymes. 24-hydroxycholesterol is the main oxysterol that is transported out of the brain and blood levels may reflect neurodegeneration. The present study aimed to elucidate the serial levels of cholesterol and cholesterol oxidation products in the brains of NP-C mice and sera of NP-C patients.

Methods: The brains of 7-week old and 12-week old NP-C mice were obtained and sub-dissected by region. Seven postnatal weeks is the time of onset of symptoms in the NPC mice. 12 week old NPC mice have marked tremor and ataxia and death usually occurs at 12–14 weeks. Serial blood samples from 3 NP-C patients ranging 8–21 in age and age matched controls were obtained. Cholesterol and oxysterol levels were evaluated with gas chromatography/mass spectrometry (GC/MS).

Results: There was no net increase in cholesterol levels in the different regions of NP-C mouse brains and in the sera of NP-C patients. An increase in 7 beta-hydroxycholesterol was observed in the diencephalon of the mice. 7 beta-hydroxycholesterol may be the oxysterol that has a pathogenic role in the neurodegeneration seen in specific regions of the brain. An increase in 24- hydroxycholesterol was observed in serial samples of sera of NP-C patients.

Conclusion: The above results showed that that there was increased cholesterol synthesis and oxysterol formation in brain regions undergoing neurodegeneration in NPC. 24 hydroxycholesterol levels were higher in patients than in controls, suggesting that this may be a useful marker for the progression of disease in patients.