The sphingolipid storage diseases are a group of ~40 genetically distinct disorders that occur with a collective frequency of 1 in 8000 live births and are often associated with devastating neurodegeneration. Among these diseases is Niemann-Pick C, an autosomal recessive disorder of lipid trafficking that produces cognitive impairment, ataxia and death, often in childhood. Most cases of this disease are caused by loss of function mutations in the Npc1 gene. Data from several laboratories demonstrate that the NPC1 protein functions in late endosome lipid sorting and vesicular trafficking, and may act as a transmembrane efflux pump. Despite these significant advances in our understanding of NPC1 function, it remains unknown how mutations in this gene cause severe neuropathology. The objective of this proposal is to develop and characterize a conditional null mutant of the mouse Npc1 gene. We expect this model will be an important resource for the neuroscience community, enabling studies characterizing the mechanism of neurodegeneration. Our central hypothesis is that conditional deletion of Npc1 exon 9 will produce a null phenotype. This hypothesis is based on the observation that deletion of exon 9 will cause a frame-shift mutation, and is expected to yield a null phenotype similar to that produced by an insertional mutation in exon 9 present in the existing constitutive Npc1 null mutant. We will test our hypothesis by characterizing mice in which loxP sites flank exon 9 of the mouse Npc1 gene. These animals will be crossed with an established mouse line expressing Cre recombinase as a transgene in oocytes, thereby causing global deletion of the floxed Npc1 allele. We are particularly well prepared to undertake the proposed research because we recently established two independent mouse lines in which one copy of the Npc1 gene has loxP sites flanking exon 9. Biochemical, histologic and behavioral approaches will be used to characterize Npc1 conditional null mice, and these animals will be made available to the neuroscience community. The relevance of the proposed studies to public health is that this animal model will be a unique resource to study the neuropathology of Niemann-Pick C and to characterize the normal function of the NPC1 protein in vivo. ? ? ?
| 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; Lieberman, Andrew P (2008) The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev Mol Med 10:e26 |
