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pp.27-33
Niemann-Pick type C disease (NPC), known an autosomal recessive disorder, is characterized by abnormal accumulation of cholesterol and glycolipid in late endosome/lysosome. The 95% case in NPC patients are caused by mutation of NPC1 gene, whose gene product is 13 transmembrane-domains and a sterol-sensing domain. The compensation of NPC1 by transgene expression in NPC1-deficient mouse recovered life span and sterility, but neurological correction incompletely, suggesting a possibility of gene therapy. Thus, in order to develop virial expression system for gene therapy of NPC, we isolated NPC1 cDNA and constructed Sindbis viral expression system for verification. NPC1 expression by Sindbis viral expression reduced the accumulation of cholesterol induced by treatment of U18666A and progesterone in both baby hamster kidney (BHK) cells and cultured hippocampal neurons. In addition, NPC1 expression increased the immunoreactivities of post-synaptic density protein 95kDa (PSD-95) in dendrites. On the basis of these results, we constructed a lentiviral vector for NPC1 expression and examined its expression in hippocampal cultured neurons.
