Niemann-Pick type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1-/- mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1-/- mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1-/- mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT) was also significantly reduced in Npc1-/- mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1+/- mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1-/- mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1-/- mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients.
Pubmed ID: 27019000 RIS Download
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The objective of this human tissue repository is to systematically collect, store, and distribute brain and other tissues for research dedicated to the improved understanding, care, and treatment of individuals with developmental disorders. Brain sections are primarily frozen in isopentane / dry ice. Tissues are stored in 10% formalin and frozen at -85 degrees C. Of special interest are individuals with Down syndrome and other chromosomal defects, mitochondrial encephalopathies, phenylketonuria and other aminoacidopathies, maternal PKU, Rett syndrome, leukodystrophies, lysosomal disorders, dyslexia, autism, and other neurodevelopmental disorders. The brain and tissue banks have extensive experience in arranging for the rapid retrieval of tissue upon the death of individuals who die while at home, in hospitals or hospice care. As a special service, the brain and tissue banks are able to assist researchers who are working with patients who intend to donate tissues at the time of their death. Immediately after retrieval of the tissue, the brain and tissue banks will forward needed tissue to the referring investigators and ensure proper storage and cataloging of any additional tissues as part of the brain and tissue banks. The recipient of tissue and the brain and tissue banks are required to sign a Tissue Transfer Agreement before any tissues are transferred.
View all literature mentionsA commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.
View all literature mentionsCell line Huh-7 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name BALB/cNctr-Npc1m1N/J from IMSR.
View all literature mentionsMus musculus with name BALB/cNctr-Npc1m1N/J from IMSR.
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