Abstract
Niemann-Pick typeC (NPC) disease is a fatal complex neurodegenerative lysosomal storage disorder caused by genetic mutations in the proteins NPC1 (95% of patients) or NPC2 that decrease intracellular cholesterol trafficking, resulting in accumulation of unesterified cholesterol and sphingolipids in lysosomal storage organelles. Unfortunately, treatment options for NPC disease are still very limited, although miglustat, which inhibits glucosylceramide synthase, thus limiting ganglioside accumulation, has been approved for treatment of NPC disease. Here we discuss advances in the understanding of NPC1 and its functions, and several new strategies for interfering with cholesterol and sphingolipid accumulation in NPC1-null mice. We also describe several recent studies demonstrating that histone deacetylase inhibitors may correct cholesterol-storage defects in human NPC1 mutant fibroblasts by increasing expression of the low-transport-activity NPC1 mutant protein. These studies may lead to development of new therapeutic approaches for treatment of NPC disease.
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