Niemann-Pick C is a recessive lipid storage disorder characterized by global progressive neurodegeneration for which there is no cure or effective treatment. About 95% of all cases of the disease are caused by mutations in the Npd gene. It is not known which cell type within the central nervous system is causing the neuronal dysfunction and degeneration seen in.this disorder, or what molecular mechanism of toxicity is exerted by loss of function mutations. It is hypothesized that functional deletion of Npd solely in neurons is responsible for the neurodegeneration in this disease, and that loss of function mutations disrupt the ER stress response. To test this hypothesis, we will compare the phenotype of existing npd-lglobal null mutant mice with conditional Npd null mutants that have been crossed to transgenic mice expressing Cre recombinase under control of the synapsin I promoter, thereby generating neuron specific null mutants. Additionally, npd-l- null mutants will be compared with transgenic mice over-expressing wild type NPC1 driven by the synapsin I promoter on the npd -I- background. In vitro investigation of the toxic effects of Npd loss of function mutations will explore the activation of the ER stress response in wild type and NPC1 deficient primary, and immortilized cells. The outcome of these studies will enhance our understanding of the mechanisms of neurodegeneration in Niemann-Pick C, and may thereby identify novel therapeutic targets for this debilitating disease.
| Elrick, Matthew J; Pacheco, Chris D; Yu, Ting et al. (2010) Conditional Niemann-Pick C mice demonstrate cell autonomous Purkinje cell neurodegeneration. Hum Mol Genet 19:837-47 |
| Pacheco, Chris D; Elrick, Matthew J; Lieberman, Andrew P (2009) Tau deletion exacerbates the phenotype of Niemann-Pick type C mice and implicates autophagy in pathogenesis. Hum Mol Genet 18:956-65 |
| Pacheco, Chris D; Elrick, Mathew J; Lieberman, Andrew P (2009) Tau normal function influences Niemann-Pick type C disease pathogenesis in mice and modulates autophagy in NPC1-deficient cells. Autophagy 5:548-50 |
| Pacheco, Chris D; Lieberman, Andrew P (2008) The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev Mol Med 10:e26 |
| Pacheco, Chris D; Kunkel, Robin; Lieberman, Andrew P (2007) Autophagy in Niemann-Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum Mol Genet 16:1495-503 |
