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We identified CD22 as a marker of dysregulated microglia in Npc1 mutant mice and subsequently demonstrated that elevated cerebrospinal fluid levels of CD22 in NPC1 patients responds to HPbetaCD administration. Collectively, these data provide the first in-depth analysis of microglia function in NPC1 and suggest possible new therapeutic approaches.
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these findings confirm the utility of high-content image-based compound screens of NPC1 patient cells and support extending the approach into larger compound collections.
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We also identified LNA ASOs targeting human host factor NPC1 and demonstrated reduced infection by chimeric vesicular stomatitis virus harboring the Ebola glycoprotein, which directly binds to NPC1 for viral infection.
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mutant NPC1 degradation is regulated by selective endoplasmic reticulum autophagy and MARCH6-dependent endoplasmic-reticulum-associated degradation
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NPC1 gene variations may predispose to common metabolic diseases by modulating steroid hormone synthesis and/or lipid homeostasis.
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Results propose that, depending on the location of the cholesterol ligand, a dynamical interface between the NPC2 and NPC1 N-terminal domain (NTD) proteins exists. Structural features of a particular interface can lower the energy barrier and stabilize the passage of the cholesterol substrate from NPC2 to NPC1(NTD).
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These data support the hypothesis that cholesterol is transported through interactions between two or more NPC1 molecules.
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Mutation in the NPC1 gene is associated with Niemann-Pick type C.
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pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency, were observed.
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Niemann-Pick C1 (NPC1) protein structures suggest mapping of all of the disease-causing mutations for future molecular insights into the pathogenesis of Niemann-Pick type C disease (NPC) disease.
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This study demonistrated that heterozygous mutations of NPC1 genes could contribute to dementia plus, at least in a subset of patients.
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Docking of the NPC1-NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and N-terminal domain cholesterol binding pockets, supporting the "hydrophobic hand-off" cholesterol transfer model.
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Taken together, these studies suggest that Ebola virus requires phosphatidylinositol (3,5) bisphosphate production in cells to promote efficient delivery to NPC1.
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identification of NPC1 and/or NPC2 mutations combined with descriptions of clinical phenotype, will improve our knowledge of pathogenic mutations and our understanding of genotype-phenotype correlations.
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Here we report a crystal structure of a large fragment of human NPC1 at 3.6 A resolution, which reveals internal twofold pseudosymmetry along TM 2-13 and two structurally homologous domains that protrude 60 A into the endosomal lumen, and we propose a model for NPC1 function in cholesterol sensing and transport.
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Sequencing of genomic DNA from GM03123 Led to the identification of a mutation in NPC1 GENE, g.41940G>C (c.1947 + 5G>C; rs770321568) (Fig. 1A), with a minor allele frequency of 0.0000082
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this case provides support for the V950M variant being sufficient for adult-onset Niemann-Pick type C disease.
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We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism's fitness.
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The mutant NPC1 did not significantly reduce cholesterol accumulation, but approximately 85% of the mutants showed reduced cholesterol accumulation when treated with vorinostat or panobinostat.
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knockdown of TMEM97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces cholesterol storage in an NPC1-dependent manner. Our findings propose TMEM97 inhibition as a novel strategy to increase residual NPC1 levels in cells and a potential therapeutic target for Niemann-Pick type C disease (NP-C).
