scholarly journals Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells

2018 ◽  
Author(s):  
Fabrizio Vacca ◽  
Stefania Vossio ◽  
Vincent Mercier ◽  
Dimitri Moreau ◽  
Shem Johnson ◽  
...  
Keyword(s):  
Storage Disease ◽  
Cell Types ◽  
Cytosolic Calcium ◽  
C Cells ◽  
Low Concentrations ◽  
Transient Rise ◽  
Type C ◽  
Niemann Pick ◽  
Lysosome Related Organelles ◽  
Cholesterol Storage

ABSTRACTIn specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in non-specialized cells, and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel MCOLN1, as well as FYCO1, the AP1 adaptor and its partner Gadkin. We conclude that endolysosomes in non-specialized cells can acquire secretory functions elicited by cyclodextrin, and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.

scholarly journals Drug-induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice

2018 ◽  
Author(s):  
Dimitri Moreau ◽  
Fabrizio Vacca ◽  
Stefania Vossio ◽  
Cameron Scott ◽  
Alexandria Colaco ◽  
...  
Keyword(s):  
Cholesteryl Ester ◽  
Free Cholesterol ◽  
C Cells ◽  
Drug Induced ◽  
Endosomal Membranes ◽  
Lysobisphosphatidic Acid ◽  
Type C ◽  
Niemann Pick ◽  
Cholesterol Storage ◽  
Histamine H3

ABSTRACTMost cells acquire cholesterol by endocytosis of circulating LDLs. After cholesteryl ester de-esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA-approved compounds in a high content, image-based screen of the endosomal lipids, lysobisphosphatidic acid and LDL-derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann-Pick type C (NPC), as well as in liver ofNpc1−/−mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.

scholarly journals Cholesterol Movement in Niemann-Pick Type C Cells and in Cells Treated with Amphiphiles

2000 ◽  
Vol 275 (23) ◽  
pp. 17468-17475 ◽  
Author(s):  
Yvonne Lange ◽  
Jin Ye ◽  
Mike Rigney ◽  
Theodore Steck
Keyword(s):  
C Cells ◽  
Type C ◽  
Niemann Pick ◽  
In Cells

scholarly journals Generation and function of astroglial lipoproteins from Niemann–Pick type C1-deficient mice

2005 ◽  
Vol 387 (3) ◽  
pp. 779-788 ◽  
Author(s):  
Barbara KARTEN ◽  
Hideki HAYASHI ◽  
Gordon A. FRANCIS ◽  
Robert B. CAMPENOT ◽  
Dennis E. VANCE ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Cell Types ◽  
Apolipoprotein A1 ◽  
Functional Assay ◽  
Atp Binding Cassette Transporter ◽  
Apo E ◽  
Type C ◽  
Niemann Pick ◽  
And Function ◽  
Endosomal System

NPC (Niemann–Pick type C) disease is a progressive neurological disorder characterized by defects in intracellular cholesterol trafficking, accumulation of cholesterol in the endosomal system and impaired cholesterol homoeostasis. Although these alterations appear to occur in all NPC1-deficient cell types, the consequences are most profound in the nervous system. Since glial cells are important mediators of brain cholesterol homoeostasis, we proposed that defective generation and/or function of lipoproteins released by glia might contribute to the neurological abnormalities associated with NPC disease. We found that, as in other cell types, Npc1−/− glia accumulate cholesterol intracellularly. We hypothesized that this sequestration of cholesterol in glia might restrict the availability of cholesterol for lipoprotein production. Cerebellar astroglia were cultured from a murine model of NPC disease to compare the lipoproteins generated by these cells and wild-type glia. The experiments demonstrate that the amount of cholesterol in glia-conditioned medium is not reduced by NPC1 deficiency. Similarly, cholesterol efflux to apo (apolipoprotein) A1 or glial expression of the transporter ATP-binding-cassette transporter A1 was not decreased by NPC1 deficiency. In addition, the ratio of apo E:cholesterol and the density distribution of lipoproteins in Npc1−/− and Npc1+/+ glia-conditioned medium are indistinguishable. Importantly, in a functional assay, apo E-containing lipoproteins generated by Npc1−/− and Npc1+/+ glia each stimulate axonal elongation of neurons by approx. 35%. On the basis of these observations, we speculate that the neuropathology characteristic of NPC disease can quite probably be ascribed to impaired processes within neurons in the brain rather than defective lipoprotein production by astroglia.

A High-Content RNAi-Screening Assay to Identify Modulators of Cholesterol Accumulation in Niemann–Pick Type C Cells

2010 ◽  
Vol 8 (3) ◽  
pp. 295-319 ◽  
Author(s):  
Shilpi Arora ◽  
Christian Beaudry ◽  
Kristen M. Bisanz ◽  
Chao Sima ◽  
Jeffrey A. Kiefer ◽  
...  
Keyword(s):  
C Cells ◽  
Cholesterol Accumulation ◽  
Screening Assay ◽  
Rnai Screening ◽  
Type C ◽  
Niemann Pick

scholarly journals A calcium message for Niemann-Pick type C

2019 ◽  
Vol 218 (12) ◽  
pp. 3890-3891
Author(s):  
Stephanie M. Cologna
Keyword(s):  
Neurodegenerative Disorder ◽  
Cellular Function ◽  
Neuronal Morphology ◽  
Calcium Distribution ◽  
Secondary Messenger ◽  
Cell Biol ◽  
Type C ◽  
Niemann Pick ◽  
Cholesterol Storage

Calcium is a ubiquitous secondary messenger that is critical for cellular function. In the highlighted article, Tiscione et al. (2019. J. Cell. Biol. https://doi.org/10.1083/jcb.201903018) describe a link between lysosomal cholesterol storage, calcium distribution alterations, and neuronal morphology in the neurodegenerative disorder Niemann-Pick type C.

Protein transduction of Rab9 in Niemann‐Pick C cells reduces cholesterol storage

2005 ◽  
Vol 19 (11) ◽  
pp. 1558-1560 ◽  
Author(s):  
Keishi Narita ◽  
Amit Choudhury ◽  
Kostantin Dobrenis ◽  
Deepak K. Sharma ◽  
Eileen L. Holicky ◽  
...  
Keyword(s):  
Protein Transduction ◽  
C Cells ◽  
Niemann Pick ◽  
Cholesterol Storage
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