This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The only colony of cats with Niemann-Pick type C disease (NPC) was moved to the School of Veterinary Medicine of the University of Pennsylvania from Colorado State University using support from the NCRR P40 grant. A point mutation in the NPC gene is responsible for clinical signs in cats. Genetic deficiency of the transmembrane NPC1 protein results in a neurovisceral cholesterol-glycosphingolipidosis, which is characterized by severe and progressive cognitive and motor deficits in addition to seizures and hepatosplenomegaly. The metabolic basis of this disease is not fully understood but deficiency in NPC1 protein results in the abnormal intracellular transport of endocytosed cholesterol, and in cellular swelling due to the storage of unesterified cholesterol and glycosphingolipids (lactosylceramide, glucosylceramide, and gangliosides) in lysosomes and late endosomes. The storage of gangliosides in neurons, specifically GM2 ganglioside, results in meganeurite formation and ectopic dendritogenesis on cortical pyramidal neurons and multipolar cells of the claustrum and amygdala. Neuropathology of the brain also includes Purkinje cell death, axonal spheroid formation of GABAergic neurons, demyelination, and neurofibrillary tangles composed of tau protein. Studies performed in the NPC cat were critical for identifying axonal spheroid formation in GABAergic neurons and the correlation of neuroaxonal dystrophy with neurological dysfunction. The feline model of NPC disease was also used to identify the late endosomal/lysosomal accumulation of GM2 and GM3 gangliosides and unesterified cholesterol as well as the association of GM2 storage with meganeurite formation and abnormal dendritogenesis. To examine the effect of glycosphingolipid storage on NPC disease, three NPC cats were previously treated with N-bultyldeoxynojirimycin (NB-DNJ), an inhibitor of all glucosylceramide-based glycosphinglipids including lactosylceramide and the gangliosides. NPC cats treated with NB-DNJ daily for 23 to 54 days showed a delay in the onset of intention tremor and ataxia, diminished Parvalbumin-positive axonal spheroids, increased numbers of Calbindin-positive Purkinje cells, a reduction in brain ganglioside accumulation, and an increase in life span. This study underscored the importance of glycosphingolipid storage on disease progression and was the first therapy to effectively ameliorate disease progression in any species with NPC disease. Studies are being performed to further define the progression of nervous system disease in the feline model NPC disease using neurological examination, electrodiagnostic testing, nuclear magnetic resonance imaging (NMR), biochemistry, and histopathology. Concurrent with these studies we are evaluating the efficacy of N-butyldeoxynojirimycin, the neurosteroid allopregnanolone, and the combination of allopregnanolone and N-butyldeoxynojirimycin, to treat nervous system disease in feline NPC. We hypothesize that the treatment of NPC cats with these drugs will delay the onset of signs of neurological dysfunction, improve electrodiagnostic and NMR abnormalities, increase lifespan, increase Purkinje cell survival, and decrease ganglioside storage in the brain.
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