title: PKC activation in Niemann pick C1 cells restores subcellular cholesterol transport.
abstract: Activation of protein kinase C (PKC) has previously been shown to ameliorate the cholesterol transport defect in Niemann Pick Type C1 (NPC1) cells, presumably by increasing the soluble levels of one of its substrates, vimentin. This activity would then restore the vimentin cycle in these cells and allow vimentin-dependent retrograde transport to proceed. Here, we further investigate the effects of PKC activation in NPC1 cells by evaluating different isoforms for their ability to solubilize vimentin and correct the NPC1 cholesterol storage phenotype. We also examine the effects of PKC activators, including free fatty acids and the PKC-specific activator diazoxide, on the NPC1 disease phenotype. Our results indicate that PKC isoforms α, βII, and ε have the greatest effects on vimentin solubilization. Furthermore, expression or activation of PKCε in NPC1 cells dramatically reduces the amount of stored cholesterol and restores cholesterol transport out of endocytic vesicles. These results provide further support for the contribution of PKCs in NPC1 disease pathogenesis and suggest that PKCs may be targeted in future efforts to develop therapeutics for NPC1 disease.
authors: Department of Genetics and Genomic Sciences, the Mount Sinai School of Medicine, New York, New York, United States of America.
authors: Farshad
authors: F
authors: Tamari
authors: Fannie W
authors: FW
authors: Chen
authors: Chunlei
authors: C
authors: Li
authors: Jagrutiben
authors: J
authors: Chaudhari
authors: Yiannis A
authors: YA
authors: Ioannou
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D016466:CHO Cells; D002457:Cell Extracts; D002784:Cholesterol / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D004951:Esterification / Q000187:drug effects; D005227:Fatty Acids / Q000494:pharmacology; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism*; D012995:Solubility; D013107:Sphingolipids / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D002457:Cell Extracts; D005227:Fatty Acids; D013107:Sphingolipids; D014746:Vimentin; D002784:Cholesterol; D011493:Protein Kinase C; C079856:RAB9A protein, human; D020691:rab GTP-Binding Proteins
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