Niemann‐Pick type C disease: molecular mechanisms and potential therapeutic approaches

Rosenbaum, Anton I.; Maxfield, Frederick R.

doi:10.1111/j.1471-4159.2010.06976.x

Cited by 211 publications

(183 citation statements)

References 70 publications

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“…5g), depolarization by Na þ efflux through TPC2 may also electrostatically facilitate fusion between two vesicular membranes as suggested by the model of Wang et al 17 Similar events may be relevant for TPC1 within the proximal endosomal pathway. Defects in the endolysosomal trafficking and cellular processing of LDL-cholesterol have been implicated in human diseases such as Niemann Pick disease and Wolman's disease (CE storage disease) where CEs accumulate in late endosomes and lysosomes due to a severely diminished activity of cholesterol export proteins NPC1 and NPC2 or lysosomal acid lipase 54 . Here, we demonstrate that loss of TPC2 results in a defect which is more distally located in the endolysosomal LDL-cholesterol trafficking pathway.…”

Section: Discussionmentioning

confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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Endolysosomal organelles play a key role in trafficking, breakdown and receptor-mediated recycling of different macromolecules such as low-density lipoprotein (LDL)-cholesterol, epithelial growth factor (EGF) or transferrin. Here we examine the role of two-pore channel (TPC) 2, an endolysosomal cation channel, in these processes. Embryonic mouse fibroblasts and hepatocytes lacking TPC2 display a profound impairment of LDL-cholesterol and EGF/EGF-receptor trafficking. Mechanistically, both defects can be attributed to a dysfunction of the endolysosomal degradation pathway most likely on the level of late endosome to lysosome fusion. Importantly, endolysosomal acidification or lysosomal enzyme function are normal in TPC2-deficient cells. TPC2-deficient mice are highly susceptible to hepatic cholesterol overload and liver damage consistent with non-alcoholic fatty liver hepatitis. These findings indicate reduced metabolic reserve of hepatic cholesterol handling. Our results suggest that TPC2 plays a crucial role in trafficking in the endolysosomal degradation pathway and, thus, is potentially involved in the homoeostatic control of many macromolecules and cell metabolites.

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Section: Discussionmentioning

confidence: 99%

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

et al. 2014

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“…Loss of these proteins causes abnormal accumulation of cholesterol in neurons and other cell types, resulting in neuronal degeneration and hepatosplenomegaly (3)(4)(5). The pathophysiology of NPC disease is complex and incompletely understood.…”

mentioning

confidence: 99%

Abnormal accumulation and recycling of glycoproteins visualized in Niemann–Pick type C cells using the chemical reporter strategy

Mbua

Flanagan-Steet

Johnson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Niemann-Pick type C (NPC) disease is characterized by impaired cholesterol efflux from late endosomes and lysosomes and secondary accumulation of lipids. Although impaired trafficking of individual glycoproteins and glycolipids has been noted in NPC cells and other storage disorders, there is currently no effective way to monitor their localization and movement en masse. Using a chemical reporter strategy in combination with pharmacologic treatments, we demonstrate a disease-specific and previously unrecognized accumulation of a diverse set of glycoconjugates in NPC1-null and NPC2-deficient fibroblasts within endocytic compartments. These labeled vesicles do not colocalize with the cholesterol-laden compartments of NPC cells. Experiments using the endocytic uptake marker dextran show that the endosomal accumulation of sialylated molecules can be largely attributed to impaired recycling as opposed to altered fusion of vesicles. Treatment of either NPC1-null or NPC2-deficient cells with cyclodextrin was effective in reducing cholesterol storage as well as the endocytic accumulation of sialoglycoproteins, demonstrating a direct link between cholesterol storage and abnormal recycling. Our data further demonstrate that this accumulation is largely glycoproteins, given that inhibitors of O-glycan initiation or N-glycan processing led to a significant reduction in staining intensity. Taken together, our results provide a unique perspective on the trafficking defects in NPC cells, and highlight the utility of this methodology in analyzing cells with altered recycling and turnover of glycoproteins.

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“…NPC disease cells display a complex cellular pathophysiology, including impaired movement of LDL-derived cholesterol from late endosomes/lysosomes to the ER 8 and the generation of non-enzymatically generated oxysterols 9 . As a consequence, the bile acid profile is altered in NPC disease 4, 5 , and this change in bile acid composition leads to a secondary suppression of the P450 gene family, as they are bile acid regulated 3 .…”

Section: Discussionmentioning

confidence: 99%

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

Nicoli¹,

Smith²,

Morris³

et al. 2017

Wellcome Open Res

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Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients.

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Niemann‐Pick type C disease: molecular mechanisms and potential therapeutic approaches

Cited by 211 publications

References 70 publications

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

High susceptibility to fatty liver disease in two-pore channel 2-deficient mice

Abnormal accumulation and recycling of glycoproteins visualized in Niemann–Pick type C cells using the chemical reporter strategy

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

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