scholarly journals Role of STARD4 and NPC1 in intracellular sterol transport

2016 ◽  
Vol 94 (6) ◽  
pp. 499-506 ◽  
Author(s):  
Frederick R. Maxfield ◽  
David B. Iaea ◽  
Nina H. Pipalia
Keyword(s):  
Mammalian Cells ◽  
Histone Deacetylase Inhibitors ◽  
Transport Pathways ◽  
Sterol Transport ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Type C ◽  
Niemann Pick ◽  
Lipid Storage Disorder

Cholesterol plays an important role in determining the biophysical properties of membranes in mammalian cells, and the concentration of cholesterol in membranes is tightly regulated. Cholesterol moves among membrane organelles by a combination of vesicular and nonvesicular transport pathways, but the details of these transport pathways are not well understood. In this review, we discuss the mechanisms for nonvesicular sterol transport with an emphasis on the role of STARD4, a small, soluble, cytoplasmic sterol transport protein. STARD4 can rapidly equilibrate sterol between membranes, especially membranes with anionic lipid headgroups. We also discuss the sterol transport in late endosomes and lysosomes, which is mediated by a soluble protein, NPC2, and a membrane protein, NPC1. Homozygous mutations in these proteins lead to a lysosomal lipid storage disorder, Niemann–Pick disease type C. Many of the disease-causing mutations in NPC1 are associated with degradation of the mutant NPC1 proteins in the endoplasmic reticulum. Several histone deacetylase inhibitors have been found to rescue the premature degradation of the mutant NPC1 proteins, and one of these is now in a small clinical trial.

Niemann-Pick Disease Type C in Adulthood - A Psychiatric and Neurological Disorder

2010 ◽  
Vol 5 (1) ◽  
pp. 83
Author(s):  
Mark Walterfang ◽  
Dennis Velakoulis ◽  
◽  
Keyword(s):  
Human Subjects ◽  
Disease Type ◽  
Loss Of Function ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Type C ◽  
Niemann Pick ◽  
Lipid Storage Disorder ◽  
Progressive Disorder ◽  
Pick Disease

Niemann-Pick disease type C (NPC) is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in eitherNpc1orNpc2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Affecting both children and adults, it exhibits a less rapid disease course in older patients, where it is characterised by slow cognitive decline, neuropsychiatric illness, ataxia and dystonia. As NPC is heterogeneous in presentation, it is often misdiagnosed as other movement or psychiatric disorders, highlighting the need for better awareness of this disease among clinicians. NPC is a progressive disorder and the only currently available disease-specific drug for its treatment is miglustat, which has shown positive outcomes in clinical studies. While other medications have been tested in animal models with encouraging results, they have yet to be trialled in human subjects.

scholarly journals Intracellular sphingosine releases calcium from lysosomes

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Doris Höglinger ◽  
Per Haberkant ◽  
Auxiliadora Aguilera-Romero ◽  
Howard Riezman ◽  
Forbes D Porter ◽  
...  
Keyword(s):  
Calcium Release ◽  
Pore Channel ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Sphingosine 1 Phosphate ◽  
Transcription Factor Eb ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease ◽  
Er Calcium

To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

A rare cause of fatal pulmonary alveolar proteinosis: Niemann-Pick disease type C2 and a novel mutation

2015 ◽  
Vol 28 (9-10) ◽  
Author(s):  
Ayhan Yaman ◽  
Fatma T. Eminoğlu ◽  
Tanıl Kendirli ◽  
Çağlar Ödek ◽  
Serdar Ceylaner ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Disease Type ◽  
Neurological Dysfunction ◽  
Lipid Storage Disease ◽  
Niemann Pick Disease ◽  
Late Endosomes ◽  
Type C ◽  
Alveolar Proteinosis ◽  
Niemann Pick ◽  
Pick Disease

AbstractNiemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is

scholarly journals Monitoring the itinerary of lysosomal cholesterol in Niemann-Pick Type C1-deficient cells after cyclodextrin treatment

2020 ◽  
Vol 61 (3) ◽  
pp. 403-412 ◽  
Author(s):  
McKenna Feltes ◽  
Sarah E. Gale ◽  
Samantha Moores ◽  
Daniel S. Ory ◽  
Jean E. Schaffer
Keyword(s):  
Isotope Labeling ◽  
Dependent Manner ◽  
Cholesterol Accumulation ◽  
Cholesterol Levels ◽  
Niemann Pick Disease ◽  
Genes Encoding ◽  
Type C ◽  
Niemann Pick ◽  
Lipid Storage Disorder ◽  
Pick Disease

Niemann-Pick disease type C (NPC) disease is a lipid-storage disorder that is caused by mutations in the genes encoding NPC proteins and results in lysosomal cholesterol accumulation. 2-Hydroxypropyl-β-cyclodextrin (CD) has been shown to reduce lysosomal cholesterol levels and enhance sterol homeostatic responses, but CD’s mechanism of action remains unknown. Recent work provides evidence that CD stimulates lysosomal exocytosis, raising the possibility that lysosomal cholesterol is released in exosomes. However, therapeutic concentrations of CD do not alter total cellular cholesterol, and cholesterol homeostatic responses at the ER are most consistent with increased ER membrane cholesterol. To address these disparate findings, here we used stable isotope labeling to track the movement of lipoprotein cholesterol cargo in response to CD in NPC1-deficient U2OS cells. Although released cholesterol was detectable, it was not associated with extracellular vesicles. Rather, we demonstrate that lysosomal cholesterol trafficks to the plasma membrane (PM), where it exchanges with lipoprotein-bound cholesterol in a CD-dependent manner. We found that in the absence of suitable extracellular cholesterol acceptors, cholesterol exchange is abrogated, cholesterol accumulates in the PM, and reesterification at the ER is increased. These results support a model in which CD promotes intracellular redistribution of lysosomal cholesterol, but not cholesterol exocytosis or efflux, during the restoration of cholesterol homeostatic responses.

scholarly journals Saccharomyces cerevisiae Npc2p Is a Functionally Conserved Homologue of the Human Niemann-Pick Disease Type C 2 Protein, hNPC2

2005 ◽  
Vol 4 (11) ◽  
pp. 1851-1862 ◽  
Author(s):  
Adam C. Berger ◽  
Thomas H. Vanderford ◽  
Kim M. Gernert ◽  
J. Wylie Nichols ◽  
Victor Faundez ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mammalian Cells ◽  
Subcellular Fractionation ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Fundamental Process ◽  
Lysosomal Accumulation ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

ABSTRACT Niemann-Pick Disease Type C (NP-C) is a fatal neurodegenerative disease, which is biochemically distinguished by the lysosomal accumulation of exogenously derived cholesterol. Mutation of either the hNPC1 or hNPC2 gene is causative for NP-C. We report the identification of the yeast homologue of human NPC2, Saccharomyces cerevisiae Npc2p. We demonstrate that scNpc2p is evolutionarily related to the mammalian NPC2 family of proteins. We also show, through colocalization, subcellular fractionation, and secretion analyses, that yeast Npc2p is treated similarly to human NPC2 when expressed in mammalian cells. Importantly, we show that yeast Npc2p can efficiently revert the unesterified cholesterol and GM1 accumulation seen in hNPC2 −/− patient fibroblasts demonstrating that it is a functional homologue of human NPC2. The present study reveals that the fundamental process of NPC2-mediated lipid transport has been maintained throughout evolution.

ANALYSIS OF CHOLESTEROL AND OXYSTEROL LEVELS IN NIEMANN PICK DISEASE TYPE C MICE AND PATIENTS

2006 ◽  
Vol 37 (S 1) ◽  
Author(s):  
S Tay ◽  
X He ◽  
AM Jenner ◽  
BS Wong ◽  
WY Ong
Keyword(s):  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease
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