Studies on neuronal death in the mouse model of Niemann-Pick C disease.
A mouse model of Niemann-Pick disease type C (NPC) carries a genetic defect that causes biochemical changes in lipid levels and a progressive neuropathology that parallels the effects of NPC disease in humans. It is a moot point whether or not the loss of Purkinje and other neuronal cells proceeds by apoptotic death. Therefore, we have introduced into these mice a transgene expressing human Bcl-2 protein which has previously been demonstrated to prevent developmental neuronal death and death induced by a variety of stimuli. The human Bcl-2 transgene was driven by the neuron-specific enolase promoter and was abundantly expressed in Purkinje and other neuronal cells. npc1(-/-)/bcl-2 transgenic mice did not show a significant delay in the onset of neurological disorders. Neuropathological examination of the npc1(-/-)/bcl-2 transgenic mice did not disclose significant differences in numbers of surviving Purkinje cells between the npc1(-/-), tg(+) and npc1(-/-), tg(-) mice. When the npc1(-/-) mice were treated with minocycline, a drug which was shown to inhibit apparent apoptotic death in other mouse models of neurological disease, no delay in onset of neurological disorders were observed in either npc1(-/-), or npc1(-/-) /mdrla(-/-) mice (mdr1a deficiency was used to enhance brain availability of minocycline). Caspase-1 levels were not altered in npc1(-/-) mice, with or without minocycline treatment. These results suggest that Purkinje cell loss in npc1(-/-) mice does not proceed by an apoptotic pathway that can be inhibited by Bcl-2 or minocycline.
Erickson
Robert P
RP
Angel Charity for Children -Wings for Genetic Research, Steele Memorial Children's Research Center, Department of Pediatrics, Section of Medical and Molecular Genetics, University of Arizona College of Medicine, Tucson, Arizona, USA.
Bernard
Ora
O
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics*; D020170:Caspase 1 / Q000032:analysis; D004195:Disease Models, Animal; D019254:Genes, bcl-2; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D009542:Niemann-Pick Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*
D000900:Anti-Bacterial Agents; D020170:Caspase 1; D008911:Minocycline