Niemann-Pick type C Disease is an autosomal recessive neurological disorder characterized by broad neurodegeneration, dementia, enlarged liver and spleen and abnormal muscle contraction. Death is caused by progressive degeneration of the brain and normally occurs in before the age of twenty. The gene responsible for the majority of disease cases is NPC1, which encodes a large transmembrane protein showing homology to the morphogen receptor patched. The cellular function of the NPC1 gene product is unknown, but mutant cells show a vesicle trafficking defect, prominently featuring an abnormal accumulation of unesterified cholesterol in late endosomes, along with numerous other endocytosed compounds. This indicates that the disease probably results from either the mislocalization or sequestration of multiple compounds or that sterol trafficking defects cause other metabolic trafficking defects. However, the relationship between sterol trafficking and neurodegeneration is not understood at this point. Two Drosophila homologs of the human NPC1 gene have been identified (termed NPC1a and NPC1b), both showing about 40% identity to the human protein. This study will characterize the function of NPC1b in Drosophila. When function of this gene is perturbed, early larval lethality is observed. Preliminary evidence suggests that the steroid hormone synthesis pathway is disrupted by mutations in NPC1b. This and other mutant phenotypes will be characterized to identify spatial and temporal requirements for NPC1b gene function. A genome-wide screen for modifiers of the phenotypes will be performed in order to identify interacting components of the sterol trafficking pathway.
| Voght, Stephen P; Fluegel, Megan L; Andrews, Laurie A et al. (2007) Drosophila NPC1b promotes an early step in sterol absorption from the midgut epithelium. Cell Metab 5:195-205 |
