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1 al cholesterol transporter, Niemann-Pick C1 (NPC1).
2 rotein that regulates the sterol transporter NPC1.
3 ncreased lifespan in mouse and cat models of NPC1.
4 helator and the only promising treatment for NPC1.
5 fered with the interaction between TIM-1 and NPC1.
6 When added to CHO cells, U-X crosslinked to NPC1.
7 entry also begins after colocalization with NPC1.
8 ther as yet unidentified receptor(s) but not NPC1.
9 the need for development of gene therapy for NPC1.
10 rom NPC2 to the transmembrane (TM) domain of NPC1.
11 sine residues in the cysteine-rich domain of NPC1.
13 rial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems fro
14 lls from patients with Niemann-Pick type C1 (NPC1), a lipid transport disorder in which increased sph
17 e genetic disorder triggered by mutations in NPC1, a multi-spanning transmembrane protein that is tra
20 pathology, we tested if disease mutations in NPC1 alter Ca(2+) signaling and neuronal plasticity.
21 lation of the non-specific phospholipase C1, NPC1, alters silicon content in nodes and husks of rice
22 es of FTY720 to mice increased expression of NPC1 and -2 in brain and liver and decreased cholesterol
24 esent a 4.4 A structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in comp
28 ight the discovery of the lysosomal proteins NPC1 and LAMP1 as intracellular receptors for Ebola viru
29 We introduced single disulfide bonds into NPC1 and NPC1L1 to explore the importance of inter-domai
32 degenerative disorder caused by mutations in NPC1 and NPC2 genes that result in an accumulation of ch
34 ta-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that export cholesterol from lyso
36 al cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann
37 type C (NPC) is associated with mutations in NPC1 and NPC2, whose gene products are key players in th
40 e integral membrane protein Niemann-Pick C1 (NPC1) and a soluble protein, Niemann-Pick C2 (NPC2).
41 NPC intracellular cholesterol transporter 1 (NPC1) and NPC2, genetic mutations of which can cause Nie
44 ession of NPC disease, double-knockout mice (Npc1(-/-)/Anxa6(-/-)) were generated and examined for li
46 otein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection.
49 e that received a single dose of AAV9-CamKII-NPC1 as neonates (2.6 x 1011GC) or at weaning (1.3 x 101
52 ice that received a single dose of AAV9-EF1a-NPC1 at weaning (1.2 x 1012GC), exhibited an increased l
53 election were assessed by the probability of NPC1 being loss-of-function mutation intolerant and Z-sc
55 suggestive of the postfusion 6-helix bundle; NPC1 binding further promoted transition to the irrevers
56 -imaging, we found that acidic pH, Ca2+, and NPC1 binding synergistically induce conformational chang
59 eduction of TMEM97, a cholesterol-responsive NPC1-binding protein, increases NPC1 levels in cells thr
61 veals how this binding site in the center of NPC1 blocks a putative lumenal tunnel linked to the SSD.
63 Here, we report a cryo-EM structure of human NPC1 bound to itraconazole, which reveals how this bindi
64 inhibiting conformational changes in primed, NPC1-bound GP that initiate fusion between the viral and
65 tation in the sterol-sensing domain (SSD) of NPC1, but not by point mutation in the N-terminal domain
67 e C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes,
70 We find that active Rab7 interacts with the NPC1 cholesterol transporter and licenses lysosomal chol
74 ound signatures of positive selection in bat NPC1 concentrated at the virus-receptor interface, with
75 contrast, P-X cross-linking was reduced when NPC1 contained a point mutation (P691S) in its putative
77 lls (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neuron
79 but the pathogenic mechanisms through which NPC1 deficiency causes neuronal dysfunction remain large
81 C1-deficient cells and brain tissue and that NPC1 deficiency leads to alterations in mitochondrial fu
83 in NPC; therefore, we analyzed the effect of NPC1 deficiency on microglia and on climbing fiber synap
85 hingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the bu
89 lesterol also accumulates in mitochondria of NPC1-deficient cells and brain tissue and that NPC1 defi
90 maCD) alleviates cholesterol accumulation in NPC1-deficient cells in spite of its low binding affinit
91 t HPgammaCD restores cellular homeostasis in NPC1-deficient cells via enhancing lysosomal dynamics an
92 had been previously shown that enrichment of NPC1-deficient cells with LBPA results in cholesterol cl
93 cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to
95 fic promoter regions of single-copy genes in NPC1-deficient cerebellum at early stages of the disease
97 lesterol showed that lysosomes purified from NPC1-deficient fibroblasts contained at least 30% less c
98 t was significantly lower after treatment of NPC1-deficient human fibroblasts with benzyl-2-acetamido
99 In the absence of galactose supplementation, NPC1-deficient ldl-D cells also transported more cholest
101 abnormal morphogenesis of the cerebellum of Npc1-deficient mice and show, for the first time, that t
102 igated amino acid metabolism in cerebella of NPC1-deficient mice at different stages of NPC disease.
105 duction of the fraction of ciliated cells in Npc1-deficient mouse brains and the human fibroblasts of
110 l mouse model faithfully recapitulates human NPC1 disease and provides a powerful tool for preclinica
111 Whereas the prominent features of human NPC1 disease are replicated in the null Npc1(-/-) mouse,
112 1-/-) displays a rapidly progressing form of NPC1 disease which is characterized by weight loss, atax
113 sing this approach, we were able to identify NPC1 disease with 91% accuracy confirming that there are
114 odel displays a less severe, delayed form of NPC1 disease with respect to weight loss, decreased moto
127 NPC1 patients and suggest that extraneuronal NPC1 expression can further augment the lifespan of the
128 Furthermore, although SARS does not require NPC1 for entry, SARS entry also begins after colocalizat
132 ease is primarily caused by mutations in the NPC1 gene and is characterized by the accumulation of un
133 While homozygous pathogenic mutations in the NPC1 gene cause Niemann-Pick type C1 disease, heterozygo
134 e recombinant protein is not possible as the NPC1 gene product is an insoluble membrane protein, whic
136 lian disorder caused by >300 variants in the NPC1 gene that disrupt cholesterol homeostasis leading t
137 rus serotype 9 (AAV9) vectors to deliver the NPC1 gene under the transcriptional control of the neuro
138 mal storage disorder due to mutations in the NPC1 gene, encoding a transmembrane protein related to t
139 caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegenera
140 the brain, and is caused by mutations in the NPC1 gene, which encodes an intracellular membrane trans
142 ur findings also highlight the importance of NPC1-GP interaction in EBOV entry and the attractiveness
143 bition of the endosomal cholesterol exporter NPC1 greatly reduced sphingosine phosphorylation in glia
144 mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion rece
145 M) proteins, integrins, and Niemann-Pick C1 (NPC1) have been reported to promote entry of ebolaviruse
147 of obesity in the general population, while NPC1 homozygous mutations may be frequent in the South A
148 ctive of the present study was to develop an NPC1 I1061T knock-in mouse in which to test proteostatic
152 NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of
154 of TMEM97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces chol
155 rt a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it i
156 In parallel, beta-cyclodextrin mediated the NPC1-independent redistribution of cholesterol within ne
171 ctivity, we tested and provide evidence that NPC1(+) LE/Lys have higher cathepsin L activity than LE,
172 an unexplored vulnerability, trafficking to NPC1(+) LE/Lys, as a therapeutic target for SARS and EBO
173 traffic late into the endocytic pathway, to NPC1(+) LE/Lys, in order to enter host cells, and that t
174 nd trafficking defect associated with I1061T-NPC1 leading to restoration of cholesterol homeostasis,
176 ion as a novel strategy to increase residual NPC1 levels in cells and a potential therapeutic target
177 l-responsive NPC1-binding protein, increases NPC1 levels in cells through a post-transcriptional mech
178 ssion of the cholesterol transporter NPC1L1 )NPC1-like intracellular cholesterol transporter 1) and c
180 raconazole binding site and the mechanism of NPC1-mediated cholesterol transport remain unknown.
181 t framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and
184 euron precursors is significantly reduced in Npc1-/- mice due to the downregulation of Shh expression
187 19 and NS11021 in a number of LSDs including NPC1, mild cases of mucolipidosis type IV (ML4) (TRPML1-
188 tion crystal structure of a complex of human NPC1-MLD and NPC2 bearing bound cholesterol-3-O-sulfate.
192 uman NPC1 disease are replicated in the null Npc1(-/-) mouse, this model is not amenable to examining
194 mouse, and delivery of the plasmid DNA, and NPC1 mRNA expression in brain, spleen, and liver were co
200 h this finding, FTY720 pretreatment of human NPC1 mutant fibroblasts restored transport of the choler
201 increased expression of NPC1 and -2 in human NPC1 mutant fibroblasts that correlated with formation o
203 97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces cholesterol
204 We aimed to investigate the prevalence of NPC1 mutations and their signatures of natural selection
206 in the prevalence of heterozygous pathogenic NPC1 mutations ranging from 0.56% in Ashkenazi Jewish to
208 d in which ebolavirus enters through a later NPC1-negative endosome that contains two-pore Ca(2+) cha
212 uring the progression of PCs degeneration in Npc1(nmf164) mice, accumulation of phagosomes and autofl
213 synaptic elements by microglia were found in Npc1(nmf164) mice, suggesting that profound developmenta
217 hich cholesterol passes through the cores of NPC1/NPC1L1 proteins; concerted movement of various doma
218 ine genes (CNN2, ITGB1, MINT2, SORL1, VLDLR, NPC1, NPC2, PSAP and SCARB2) in astrocytes significantly
223 istered weekly beginning at 6-7 weeks in the NPC1(-/-) null mouse, and delivery of the plasmid DNA, a
227 8.0 kb plasmid DNA encoding the 3.9 kb human NPC1 open reading frame, under the influence of a 1.5 kb
228 sosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal
229 e defects in the endosomal-lysosomal protein NPC1 or NPC2 cause intracellular accumulation of unester
230 e (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of chol
231 degenerative disorder caused by mutations in NPC1 or NPC2 with decreased functions leading to lysosom
233 this interaction, in which mAbs specific for NPC1 or the GP receptor-binding site are coupled to a mA
238 erapy may represent a therapeutic option for NPC1 patients and suggest that extraneuronal NPC1 expres
241 o-function-to-structure relationships of the NPC1 polypeptide fold required for membrane trafficking
243 ntry occurs upon arrival in Niemann-Pick C1 (NPC1)-positive endolysosomes (LE/Lys), we propose that t
244 nd in the human population inhibit export of NPC1 protein from the endoplasmic reticulum (ER) and/or
245 These experiments support a model in which NPC1 protein functions to transfer cholesterol past a ly
247 pies directed at stabilization of the mutant NPC1 protein reduce cholesterol storage in fibroblasts b
250 l from lysosomes into the cytoplasm requires NPC1 protein; NPC1L1 mediates uptake of dietary choleste
251 d the hypothesis that Niemann-Pick type C 1 (NPC1) protein aids the transfer of low density lipoprote
254 llular receptors, including Niemann-Pick C1 (NPC1) protein, and GP2 is responsible for low pH-induced
256 GP, and its entry receptor Niemann-Pick C1 (NPC1) provides an attractive target for such mAbs but is
261 ed to wild-type, whereas RNAi suppression of NPC1 resulted in the opposite changes to those of NPC1-O
262 h AAV9-EF1a-NPC1, as compared to AAV9-CamKII-NPC1, resulted in significantly increased survival (mean
266 lysosomal cholesterol efflux, we found that NPC1's N-terminal domain need not release from the rest
268 stricted to cells that have primate-specific NPC1 sequences at the EBOV interface, suggesting that th
269 of cholesterol from lysosomes by U18666A or NPC1 siRNA prevents ER cholesterol from increasing and,
270 these difficulties, the search for a novel, NPC1-specific biomarker (or set of biomarkers) is a topi
271 revious studies suggest that mutation of the NPC1-SSD or the addition of the anti-fungal drug itracon
272 f the NPC1-NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tun
273 also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and
274 inding Niemann-Pick disease type C1 protein (NPC1) suggests how the modified binding surface of Juno
277 g at least one copy of the I1061T variant of NPC1, the most common disease-associated mutation leadin
278 Compared with the Npc1(-/-) mouse, this Npc1(tm(I1061T)Dso) model displays a less severe, delaye
279 on an amino acid residue-by-residue basis in NPC1 to differentially regulate variant trafficking, sta
281 beta-cyclodextrin, by restoring a functional NPC1 to the cholesterol managing compartment as an adjun
284 s between blood plasma samples acquired from NPC1 (untreated and miglustat treated), heterozygote, an
285 ps a plasmid DNA approach to gene therapy of NPC1 using Trojan horse liposomes (THLs), wherein the pl
289 sceptibility in bats, and suggests that some NPC1 variations reflect host adaptations to reduce filov
290 ast, expression of Mer, integrin alphaV, and NPC1 was required for efficient GP-mediated transduction
291 t the potential efficacy of gene therapy for NPC1, we constructed adeno-associated virus serotype 9 (
292 2013, and Jan 19, 2015, 32 participants with NPC1 were assessed for eligibility at the National Insti
295 nted by deletion of the N-terminal domain of NPC1, which contains the initial binding site for choles
296 NPC) is caused in most cases by mutations in NPC1, which encodes the late endosomal NPC1 protein.
297 ase-linked mutation is the I1061T variant of NPC1, which exhibits defective folding and trafficking f
298 amino acid change in the filovirus receptor, NPC1, which greatly reduces the affinity of EBOV-NPC1 in
299 In this study, we demonstrate that TIM-1 and NPC1, which serve as attachment and fusion receptors for
300 ly intrathecal HPbetaCD to participants with NPC1 with neurological manifestation at the National Ins