Studies on neuronal death in the mouse model of Niemann‐Pick C disease

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Abstract
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.