Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking

Chang, Ta−Yuan; Reid, Patrick; Sugii, Shigeki; Ohgami, Nobutaka; Cruz, Jonathan C.; Chang, Catherine C.Y.

doi:10.1074/jbc.r400040200

Cited by 149 publications

(112 citation statements)

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“…Niemann-Pick C (NPC) 1 is a homologue of NPC1L1 (8,9). NPC1 and another protein, NPC2, are required for transporting the LDL-derived cholesterol out of late endosomes/lysosomes (10). Mutation of the npc1 or npc2 genes leads to the Niemann-Pick Type C disease, a fatal hereditary disorder characterized by accumulation of cholesterol in late endosomes/ lysosomes (9,11).…”

mentioning

confidence: 99%

The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

Zhang

et al. 2011

Journal of Biological Chemistry

100

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Niemann-Pick C1-like 1 (NPC1L1) is a multitransmembrane protein playing a crucial role in dietary and biliary cholesterol absorption. Cholesterol promotes the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains, which is an early step in cholesterol uptake. How cholesterol is sensed in this step is unknown. Here, we find that the N-terminal domain (NTD) of NPC1L1 binds cholesterol. Mutation of residue Leu-216 in NPC1L1-NTD eliminates cholesterol binding, decreases the formation of NPC1L1-flotillin-cholesterol membrane microdomains, and prevents NPC1L1-mediated cholesterol uptake in culture cells and mice livers. NPC1L1-NTD specifically binds cholesterol but not plant sterols, which may account for the selective cholesterol absorption in intestine. Furthermore, 25-or 27-hydroxycholesterol competes with cholesterol to bind NPC1L1-NTD and inhibits the cholesterol induced endocytosis of NPC1L1. Together, these results demonstrate that plasma membrane-localized NPC1L1 binds exogenous cholesterol via its NTD, and facilitates the formation of NPC1L1-flotillin-cholesterol membrane microdomains that are then internalized into cells through the clathrin-AP2 pathway. Our study uncovers the mechanism of cholesterol sensing by NPC1L1 and proposes a mechanism for selective cholesterol absorption.NPC1L1 is a multiple transmembrane protein that is essential for dietary cholesterol absorption and biliary cholesterol reabsorption (1-3). Our previous studies have revealed that NPC1L1 can move between the endocytic recycling compartment (ERC) 4 and plasma membrane (PM) (4). Cholesterol depletion induces the export of NPC1L1 from ERC to PM in a myosin Vb-rab11a-rab11-FIP2-dependent manner (5, 6). Reversely, cholesterol replenishment promotes the formation of cholesterol-enriched membrane microdomains containing NPC1L1 and flotillins, named NPC1L1-flotillin-cholesterol membrane microdomains (7). These microdomains are in turn internalized through clathrin-AP2-mediated endocytosis and, therefore, lead to the internalization of NPC1L1 and ensure the efficient cholesterol uptake (7). It's still a mystery how cholesterol is sensed to initiate the formation and endocytosis of NPC1L1-flotillin-cholesterol membrane microdomains. Niemann-Pick C (NPC) 1 is a homologue of NPC1L1 (8, 9). NPC1 and another protein, NPC2, are required for transporting the LDL-derived cholesterol out of late endosomes/lysosomes (10). Mutation of the npc1 or npc2 genes leads to the Niemann-Pick Type C disease, a fatal hereditary disorder characterized by accumulation of cholesterol in late endosomes/ lysosomes (9, 11). NPC1 and NPC1L1 show the similar protein topology. Both of them have 13 transmembrane helices containing a sterol-sensing domain, a large luminal N-terminal domain (NTD), and two large luminal loops (12, 13). Recently, it has been shown that the NTD of NPC1 directly binds cholesterol (14). The crystal structure of the cholesterol-bound NPC1-NTD reveals that the cholesterol molecule is embedded in the binding pocket with an ...

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confidence: 99%

The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

Zhang

et al. 2011

Journal of Biological Chemistry

100

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“…Hastalar ilk iki yaşa kadar genellikle normal gelişim gösterirler. NPH tip A kadar belirgin olmayan hepatosplenomegali vardır [1,5,10]. Ekzojen kolesterolün hücre içi metabolizmasındaki bir hata nedeniyle esterleşmeyen kolesterolün lizozomlarda birikmesi ile karakterizedir.…”

Section: Discussionunclassified

Niemann-Pick hastalığı tip A ve tip B: İki olgu sunumu

Zorlu¹,

Uçar²,

Yaralı³

et al. 2014

MMJ

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Niemann-Pick hastalığı (NPH), sfingomyelinaz enzim eksikliğine bağlı olarak vücudun çeşitli organlarında, özellikle retiküloendotelyal sistem ve santral sinir sisteminde, intraselüler sfingomyelin ve kolesterol birikimi ile karakterize, otozomal resesif geçişli, nadir görülen bir lizozomal lipid depo hastalığıdır [1]. Genetik, klinik ve biyokimyasal heterojeniteye sahip hastalığın altı tipi tanımlanmıştır: Tip A-Akut nöronopatik form, Tip B-Kronik visseral form, Tip C-Kronik nöronopatik form daha iyi tanımlanmış formlardır. Tip A tüm hastaların %85' ini oluşturur [1,2].Niemann-Pick hastalığında sıklıkla nörolojik ve gastrointestinal sistem bulguları, büyüme-gelişme geriliği, göz bulguları, nadiren de solunum sistemi, cilt ve kardiyak bulgular görülür. Tanı, sfingomyelinaz aktivitesinin tespiti ve Niemann-Pick hücrelerinin kemik iliği incelemesinde gösterilmesi ile konur [1,3]. Burada NPH tanısı alan iki farklı tipte (tip A ve B) olgu sunuldu. Olgu SunumuOlgu 1: 15 aylık erkek hasta, karın şişliği, yürüyememe, konuşamama şikayetleriyle başvurdu. Öyküsünden aralarında üçüncü derece akrabalık olan anne babanın ikinci çocukları olarak, miadında, hastanede, 3800 gr olarak, normal yol ile doğduğu, iki kez pnömoni nedeniyle hastanede yattığı öğrenildi. Kardeş ölümü ve ailede benzer hastalık öyküsü yoktu. Bir aylıkken karın şişliği başlamış, altı aylıkken karaciğer ve dalakta büyüme farkedilmiş ve gittikleri merkez tarafından tetkikleri yapılmış; alfa-1 antitripsin, ter testi, viral serolojiler, immünglobulin M-A-G-E, göz muayenesi, kemik iliği aspirasyonu incelemesi, idrar ve kan aminoasitleri ve tandem mass incelemeleri normal bulunmuş. Karaciğer biopsisinde hepatositlerde sekonder lizozomlar çok sayıda, geniş ve birleşmiş olarak izlenmiş ve hepatositlerde yoğun lipid damlacıkları görülmüş. Nöromotor gelişim öyküsünde; dört aylıkken ÖZET Niemann-Pick hastalığı, belirli dokularda, özellikle retiküloendotelyel hücrelerde, sfingolipidlerin biriktiği, konjenital lipidoz grubundan otozomal resesif kalıtılan bir hastalıktır. Klinik fenotip olarak akut neonatal formdan geç başlangıçlı erişkin forma kadar aralığı oldukça değişkendir. Karaciğer ve dalak büyüklüğü şikayetiyle kliniğimize başvuran Niemann-Pick hastalığı tip A ve tip B tanıları alan iki hasta sunuldu.

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“…The relationship between the cellular glycosphingolipid accumulation and cellular cholesterol accumulation is complex (discussed in (Chang et al, 2005b)). In mutant NPC1 cells, Reagan and colleagues showed that cholesterol accumulation inhibits lysosomal sphingomyelinase activity (Reagan et al, 2000); Salvioli and colleagues (Salvioli et al, 2004) showed that cholesterol accumulation inhibits two additional lysosomal enzymes involved in the degradation of glycosphingolipids.…”

Section: Discussionmentioning

confidence: 99%

“…Mouse models for the NPC disease are available (Chang et al, 2005b;Patterson et al, 2001). These mice show various pathological progressions in the CNS, in manners very similar to those of the human NPC disease.…”

Section: Introductionmentioning

confidence: 99%

“…It is characterized by the cellular accumulation of unesterified cholesterol, sphingomyelin, glycolipids, and other lipids within the endosomal/lysosomal system of various tissues including liver, spleen, and the central nervous system (CNS) (reviewed in (Patterson et al, 2001;Chang et al, 2005a)). The disease can be caused by mutations in one of two genetic loci, NPC1 and NPC2.…”

Section: Introductionmentioning

confidence: 99%

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Partial blockage of sterol biosynthesis with a squalene synthase inhibitor in early postnatal Niemann-Pick type C npcnih null mice brains reduces neuronal cholesterol accumulation, abrogates astrogliosis, but may inhibit myelin maturation

Reid

Song

Vanier

et al. 2008

Journal of Neuroscience Methods

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Niemann-Pick C disease (NPC) is a fatal, neurovisceral genetic disorder. Cell culture studies showed that NPC1 or NPC2 mutations cause malfunctions in cellular cholesterol trafficking and lead to accumulation of cholesterol and other lipids in the late endo/lysosomes. Previous work showed that neuronal cholesterol accumulation occurs in the brains of young postnatal NPC1-/-mice. Here, to evaluate the potential of partial blockage of cholesterol biosynthesis as a therapy for the NPC disease, we first developed a simple method to monitor the relative rates of lipid biosynthesis in mice brains. We next administered squalene synthase inhibitor (SSI) CP-340868 to young mice. The results show that treating 8-day-old NPC1-/-mice with CP-340868 for six days significantly inhibits cholesterol biosynthesis in the mice brains. It reduces neuronal cholesterol accumulation, reduces GM3 ganglioside accumulation, and diminishes astrogliosis in the brain. These results suggest that neuronal cholesterol accumulation contributes to early pathogenesis in the NPC1-/-mice brains. The SSI treatment also reduced brain galactolipid content, suggesting that blocking endogenous cholesterol synthesis in the young mice brains may disrupt the normal myelin maturation processes. The methods described in the current work have general applicability for lipid metabolism studies in mice brains in various pathophysiological conditions.

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Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking

Cited by 149 publications

References 61 publications

The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

The N-terminal Domain of NPC1L1 Protein Binds Cholesterol and Plays Essential Roles in Cholesterol Uptake

Niemann-Pick hastalığı tip A ve tip B: İki olgu sunumu

Partial blockage of sterol biosynthesis with a squalene synthase inhibitor in early postnatal Niemann-Pick type C npcnih null mice brains reduces neuronal cholesterol accumulation, abrogates astrogliosis, but may inhibit myelin maturation

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