Amelioration of enteric neuropathology in a mouse model of Niemann-Pick C by Npc1 expression in enteric glia.

Niemann-Pick C (NPC) disease is an autosomal recessive, lethal, neurodegenerative disorder caused by mutations in NPC1. By using the glial fibrillary acidic protein (GFAP) promoter, we demonstrated previously that astrocyte-specific expression of Npc1 decreased neuronal storage of cholesterol in Npc1(-/-) mice; reduced numbers of axonal spheroids; and produced less degeneration of neurons, reactive astrocytes, and loss of myelin tracts in the central nervous system. GFAP-Npc1, Npc1(-/-) mice exhibited markedly enhanced survival, and death was not associated with the severe terminal weight loss observed in Npc1(-/-) mice. Intestinal transit is delayed in Npc1(-/-) mice but is normal in GFAP-NPC1, Npc1(-/-) until late in the course of their disease. Because glia play an important role in the enteric nervous system, we studied morphology and cholesterol content of intestines from Npc1(-/-) mice and examined the effect of GFAP-promoted restoration of Npc1 in enteric glia. Although the number of neurons was not altered, the total amount of cholesterol stored in the small intestine was decreased, as were the number of neurons with inclusions and the number of inclusions per neuron. We conclude that expression of Npc1 by enteric glial cells can ameliorate the enteric neuropathology, and we speculate that dysfunction of the enteric nervous system contributes to the retarded intestinal transit, weight loss, and demise of Npc1(-/-) mice.