COMMENTARY

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

Stephen L. Sturleya, Marc C. Pattersonb, and Peter Pentchevc,1 aDepartment of Pediatrics and Institute of Human Nutrition, Columbia University Medical Center, 630 West 168th Street, New York, NY 10032; bDivision of Child and Adolescent Neurology, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905; and cMetabolic Modeling Services, 4217 Peterborough Road, West Lafayette, IN 47906-5680

he interorganellar transfer of hypothesis can now be tested in the showed that LXR agonists increase cho- lipids, particularly cholesterol, NPC2 mouse model (5). CYCLO may lesterol loss from the brain without al- is imperfectly understood but is provide a useful tool to probe the inter- tering synthesis (9). Neither of these a key component of membrane action of NPC1 and NPC2 proteins, physiological manipulations appeared to Thomeostasis as shown by the lethal dis- which modulate the relocation of lysoso- alter cholesterol permeability across the orders that are associated with its de- mal cholesterol to regulatory cytosolic limiting membrane of the lysosomes in rangement. For unknown reasons, the pools. which the cholesterol was trapped; this neuron is particularly susceptible to ex- may explain their limited effects. The cessive lipid accumulation. In the case Role of Cholesterol in NP-C unique aspect of the current study is of Niemann-Pick type C (NPC) disease, In a series of earlier publications, the that administration of CYCLO to the a lysosomal lipid storage disorder, the Dietschy and Repa laboratories ele- npc1Ϫ/Ϫ mice appeared to reestablish accumulation of cholesterol and sphin- gantly demonstrated the central role sterol movement out of lysosomes. golipids manifests as a fatal neuro- that defective cholesterol trafficking out visceral degenerative disorder. Liu et al. of lysosomes plays in the cellular patho- Mechanism of CYCLO Action (1) report in this issue of PNAS that genesis of this disorder in the NPC The next critical question is how CY- defective trafficking of cholesterol and mouse. (6). The current observations CLO might induce such responses in disease severity can be circumvented in suggest that this offending metabolite these animals. An important and some- the npc1Ϫ/Ϫ mouse by a single and has been sufficiently mobilized in a key what surprising observation in the timely injection of the cholesterol- tissue, such as the brain, to impact current study was that CYCLO adminis- binding agent, 2-hydroxypropyl-ß- tration to normal mice showed no effect cyclodextrin (CYCLO). on whole body cholesterol turnover. In CYCLO may provide a the npc1Ϫ/Ϫ mouse treated with CYCLO Genes of the NP-C Pathway the 3 cellular signals of rapid lysosomal Two clinically and pathologically indis- useful tool to probe the cholesterol depletion into the cytosolic tinguishable diseases (NPC1 and NPC2) compartment were clearly documented: are associated with mutations in either interaction of NPC1 and (i) an immediate increase in cholesteryl of two distinct genes (NPC1 or NPC2). esters, (ii) a suppression of the SREBP In vitro studies have documented bind- NPC2 proteins. target genes, and (iii) an up-regulation ing of cholesterol to both NPC1 (2) and of LXR target genes. It is clear from NPC2 (3) proteins, albeit with marked this and other studies that the timing differences in affinity. The most recent disease. However, the possible patho- of CYCLO administration is critical. data suggest that cholesterol is ex- genic role of many other lipids as addi- Seven-day-old mice (perhaps especially changed in a tandem fashion between tional ‘‘offending metabolites’’ remains those with NPC disease) may have a these 2 proteins although the specter of unsettled (6, 7). Sterol and sphingolipids more permeable blood–brain barrier a third protein has recently loomed (4) frequently colocalize with important that becomes progressively less perme- consistent with the observation that mu- consequences, and may even be cotrans- able during development. Liu et al. (1) tations cannot be identified in NPC1 or ported. The authors have not yet moni- show remarkable lessening of the cho- NPC2 in some patients with NPC dis- tored other lipids that are known to lesterol burden from a single adminis- ease. In vivo studies, which largely use accumulate in NPC disease. tration at this juncture that continued to the npc1-null mouse model, have dem- The effect of CYCLO in NPC mice be effective despite the virtual disap- onstrated that all organ systems are af- has exciting heuristic implications for a pearance of CYCLO from the animal fected by NPC mutations, but only broad spectrum of important mechanis- within 24 h (only 9% of the adminis- agents that appear to cross the blood– tic and perhaps, ultimately, therapeutic tered dose remained in the animals, at brain barrier alleviate neurodegenera- questions. Lessening the cholesterol this time point). Whether this reflects tion and extend lifespan (1). The au- metabolic burden in the NPC mouse has an epigenetic effect of CYCLO treat- thors suggest that the cholesterol- been shown to clearly moderate the se- ment or a singular salvage event that binding properties of CYCLO may allow verity of the disorder in this model (1), transiently spares neurons from the rav- this agent to substitute for dysfunctional thereby indicating that reversing the ages of loss of these functional NPC1/ NPC1 protein in the npc1-null mouse. sterol-trafficking defect itself might im- NPC2 proteins, remains to be addressed. In solubilizing the acid lipase-generated prove the course of NPC. Early support free cholesterol that becomes trapped in for this notion was found in a study re- lysosomes, CYCLO is also taken up into porting that blocking chylomicron deliv- Author contributions: S.L.S., M.C.P., and P.P. wrote the paper. organelles by bulk phase endocytosis ery to the liver lowers cholesterol con- The authors declare no conflict of interest. and may then be able to transfer the tent and improves liver function. See companion article on page 2377. cholesterol to the NPC2 protein pool, However, neither CNS lipid storage nor 1To whom correspondence should be addressed. E-mail: thus reestablishing transfer through the disease symptoms were ameliorated by [email protected]. NPC pathway. This novel and enticing this intervention (8). A second study © 2009 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0812934106 PNAS ͉ February 17, 2009 ͉ vol. 106 ͉ no. 7 ͉ 2093–2094 Downloaded by guest on September 28, 2021 The bottom line is that a single applica- organ, including the central nervous sys- human NPC disease remains to be fully tion of CYCLO and the ensuing homeo- tem, as a function of age? Would re- established. Such a role has been sug- static responses led to net loss of sterol peated injections of CYCLO cure the gested from documentation of delayed from the whole animal and a marked liver and lung, but not the CNS? Would appearance of LDL-derived cholesterol improvement in the clinical state of the direct administration of cyclodextrin in the plasma in NPC patients (10). At mutant mouse. into the CNS improve half-life and re- present, CYCLO represents an exciting Many critical questions must be an- sponse? Finally, it is important to bear tool for exploring the cell biology of swered before CYCLO or a related in mind that contrary to the NPC NPC disease that needs further experi- compound reaches the clinic. What are mouse model where cholesterol has mental validation in animal models the permeability coefficients for CY- been shown to act as an offending me- before it is considered as a therapeutic CLO across the capillary beds of every tabolite, a similar role for this sterol in agent.

1. Liu B, et al. (2009) Reversal of defective lysoso- 4. Infante RE, et al. (2008) NPC2 facilitates bidirectional 8. Beltroy EP, Liu B, Dietschy JM, Turley SD (2007) Lysoso- mal transport in NPC disease ameliorates liver transfer of cholesterol between NPC1 and lipid bilay- mal unesterified cholesterol content correlates with dysfunction and neurodegeneration in the ers, a step in cholesterol egress from lysosomes. Proc liver cell death in murine Niemann-Pick type C disease. npc1Ϫ/Ϫ mouse. Proc Natl Acad Sci USA 106:2377– Natl Acad Sci USA 105:15287–15292. J Lipid Res 48:869–881. 2382. 5. Sleat DE, et al. (2004) Genetic evidence for nonredundant 9. Repa JJ, et al. (2007) Liver X receptor activation en- 2. Infante RE, et al. (2008) Purified NPC1 protein. I. functional cooperativity between NPC1 and NPC2 in lipid hances cholesterol loss from the brain, decreases neu- Binding of cholesterol and oxysterols to a 1278- transport. Proc Natl Acad Sci USA 101:5886–5891. roinflammation, and increases survival of the NPC1 amino acid membrane protein. J Biol Chem 6. Liu B, Li H, Repa JJ, Turley SD, Dietschy JM (2008) mouse. J Neurosci 27:14470–14480. 283:1052–1063. Genetic variations and treatments that affect the lifes- 10. Shamburek RD, et al. (1997) Intracellular trafficking of 3. Liou HL, et al. (2006) NPC2, the protein deficient in pan of the NPC1 mouse. J Lipid Res 49:663–669. the free cholesterol derived from LDL cholesteryl ester Niemann-Pick C2 disease, consists of multiple glyco- 7. Lloyd-Evans E, et al. (2008) Niemann-Pick disease type is defective in vivo in Niemann-Pick C disease: Insights forms that bind a variety of sterols. J Biol Chem C1 is a sphingosine storage disease that causes dereg- on normal metabolism of HDL and LDL gained from the 281:36710–36723. ulation of lysosomal calcium. Nat Med 14:1247–1255. NP-C mutation. J Lipid Res 38:2422–2435.

2094 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0812934106 Sturley et al. Downloaded by guest on September 28, 2021