Cyclodextrin induces calcium-dependent lysosomal exocytosis.
Cyclodextrins (CDs) have long been used to manipulate cellular cholesterol levels both in vitro and in vivo, but their direct effects at a cellular level are not well characterized. Recently, CDs have garnered much interest because of their ability to clear stored cholesterol from Niemann Pick Type C (NPC) cells and markedly prolong the life of NPC1 disease mice. Here, we investigate the hypothesis that treatment with 2-hydroxypropyl- β-cyclodextrin (HPB-CD) stimulates lysosomal exocytosis in a calcium-enhanced manner. We propose that this exocytosis is the mechanism by which HPB-CD ameliorates the endolysosomal cholesterol storage phenotype in NPC cells. These findings have significant implications for the use of HPB-CD in biochemical assays and data interpretation as well as for their use for the treatment for NPC and other disorders.
Department of Genetics and Genomic Sciences, The Mount Sinai School of Medicine, New York, New York, USA.
Fannie W
FW
Chen
Chunlei
C
Li
Yiannis A
YA
Ioannou
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D005079:Excipients / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects*; D055354:Exosomes / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D000077296:Niemann-Pick C1 Protein; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
D005079:Excipients; D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D049452:Green Fluorescent Proteins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium