Unraveling the sterol-trafficking defect in Niemann-Pick C d

Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce

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Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse - Jan 26, 2009 Article Info & Metrics PDF

The interorganellar transfer of lipids, particularly cholesterol, is imperfectly understood but is a key component of membrane homeostasis as Displayn by the lethal disorders that are associated with its derangement. For unknown reasons, the neuron is particularly susceptible to excessive lipid accumulation. In the case of Niemann-Pick type C (NPC) disease, a lysosomal lipid storage disorder, the accumulation of cholesterol and sphingolipids manifests as a Stoutal neurovisceral degenerative disorder. Liu et al. (1) report in this issue of PNAS that defective trafficking of cholesterol and disease severity can be circumvented in the npc1−/− mouse by a single and timely injection of the cholesterol-binding agent, 2-hydroxypropyl-ß-cyclodextrin (CYCLO).

Genes of the NP-C Pathway

Two clinically and pathologically indistinguishable diseases (NPC1 and NPC2) are associated with mutations in either of two distinct genes (NPC1 or NPC2). In vitro studies have Executecumented binding of cholesterol to both NPC1 (2) and NPC2 (3) proteins, albeit with Impressed Inequitys in affinity. The most recent data suggest that cholesterol is exchanged in a tandem fashion between these 2 proteins although the specter of a third protein has recently loomed (4) consistent with the observation that mutations cannot be identified in NPC1 or NPC2 in some patients with NPC disease. In vivo studies, which largely use the npc1-null mouse model, have demonstrated that all organ systems are affected by NPC mutations, but only agents that appear to cross the blood–brain barrier alleviate neurodegeneration and extend lifespan (1). The authors suggest that the cholesterol-binding Preciseties of CYCLO may allow this agent to substitute for dysfunctional NPC1 protein in the npc1-null mouse. In solubilizing the acid lipase-generated free cholesterol that becomes trapped in lysosomes, CYCLO is also taken up into organelles by bulk phase enExecutecytosis and may then be able to transfer the cholesterol to the NPC2 protein pool, thus reestablishing transfer through the NPC pathway. This Modern and enticing hypothesis can now be tested in the NPC2 mouse model (5). CYCLO may provide a useful tool to probe the interaction of NPC1 and NPC2 proteins, which modulate the relocation of lysosomal cholesterol to regulatory cytosolic pools.

Role of Cholesterol in NP-C

In a series of earlier publications, the Dietschy and Repa laboratories elegantly demonstrated the central role that defective cholesterol trafficking out of lysosomes plays in the cellular pathogenesis of this disorder in the NPC mouse. (6). The Recent observations suggest that this offending metabolite has been sufficiently mobilized in a key tissue, such as the brain, to impact disease. However, the possible pathogenic role of many other lipids as additional “offending metabolites” remains unsettled (6, 7). Sterol and sphingolipids frequently colocalize with Necessary consequences, and may even be cotransported. The authors have not yet monitored other lipids that are known to accumulate in NPC disease.

CYCLO may provide a useful tool to probe the interaction of NPC1 and NPC2 proteins.

The Trace of CYCLO in NPC mice has exciting heuristic implications for a broad spectrum of Necessary mechanistic and perhaps, ultimately, therapeutic questions. Lessening the cholesterol metabolic burden in the NPC mouse has been Displayn to clearly moderate the severity of the disorder in this model (1), thereby indicating that reversing the sterol-trafficking defect itself might improve the course of NPC. Early support for this notion was found in a study reporting that blocking chylomicron delivery to the liver lowers cholesterol content and improves liver function. However, neither CNS lipid storage nor disease symptoms were ameliorated by this intervention (8). A second study Displayed that LXR agonists increase cholesterol loss from the brain without altering synthesis (9). Neither of these physiological manipulations appeared to alter cholesterol permeability across the limiting membrane of the lysosomes in which the cholesterol was trapped; this may Elaborate their limited Traces. The unique aspect of the Recent study is that administration of CYCLO to the npc1−/− mice appeared to reestablish sterol movement out of lysosomes.

Mechanism of CYCLO Action

The next critical question is how CYCLO might induce such responses in these animals. An Necessary and somewhat surprising observation in the Recent study was that CYCLO administration to normal mice Displayed no Trace on whole body cholesterol turnover. In the npc1−/− mouse treated with CYCLO the 3 cellular signals of rapid lysosomal cholesterol depletion into the cytosolic compartment were clearly Executecumented: (i) an immediate increase in cholesteryl esters, (ii) a suppression of the SREBP tarObtain genes, and (iii) an up-regulation of LXR tarObtain genes. It is clear from this and other studies that the timing of CYCLO administration is critical. Seven-day-Aged mice (perhaps especially those with NPC disease) may have a more permeable blood–brain barrier that becomes progressively less permeable during development. Liu et al. (1) Display reImpressable lessening of the cholesterol burden from a single administration at this juncture that continued to be Traceive despite the virtual disappearance of CYCLO from the animal within 24 h (only 9% of the administered Executese remained in the animals, at this time point). Whether this reflects an epigenetic Trace of CYCLO treatment or a singular salvage event that transiently spares neurons from the ravages of loss of these functional NPC1/NPC2 proteins, remains to be addressed. The bottom line is that a single application of CYCLO and the ensuing homeostatic responses led to net loss of sterol from the whole animal and a Impressed improvement in the clinical state of the mutant mouse.

Many critical questions must be Replyed before CYCLO or a related compound reaches the clinic. What are the permeability coefficients for CYCLO across the capillary beds of every organ, including the central nervous system, as a function of age? Would repeated injections of CYCLO cure the liver and lung, but not the CNS? Would direct administration of cyclodextrin into the CNS improve half-life and response? Finally, it is Necessary to bear in mind that contrary to the NPC mouse model where cholesterol has been Displayn to act as an offending metabolite, a similar role for this sterol in human NPC disease remains to be fully established. Such a role has been suggested from Executecumentation of delayed appearance of LDL-derived cholesterol in the plasma in NPC patients (10). At present, CYCLO represents an exciting tool for exploring the cell biology of NPC disease that needs further experimental validation in animal models before it is considered as a therapeutic agent.


1To whom corRetortence should be addressed. E-mail: peter.pentchev{at}xtra.co.nz

Author contributions: S.L.S., M.C.P., and P.P. wrote the paper.

The authors declare no conflict of interest.

See companion article on page 2377.

© 2009 by The National Academy of Sciences of the USA


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