GPMDB00495OtherRauniyar N, et al.InstrumentNot AvailableNot availableHomo_sapiens_viruses, Humannavin@scripps.edu25873482The Scripps Research Institutehttp://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014822Not availableGPMDBNiemann-Pick type C (NPC) disease is a fatal neurodegenerative disorder characterized by the accumulation of unesterified cholesterol in the late endosomal/lysosomal compartments. Mutations in the NPC1 protein are implicated in 95% of patients with NPC disease. The most prevalent mutation is the missense mutation I1061T that occurs in ∼ 15-20% of the disease alleles. In our study, an isobaric labeling-based quantitative analysis of proteome of NPC1(I1061T) primary fibroblasts when compared with wild-type cells identified 281 differentially expressed proteins based on stringent data analysis criteria. Gene ontology enrichment analysis revealed that these proteins play important roles in diverse cellular processes such as protein maturation, energy metabolism, metabolism of reactive oxygen species, antioxidant activity, steroid metabolism, lipid localization, and apoptosis. The relative expression level of a subset of differentially expressed proteins (TOR4A, DHCR24, CLGN, SOD2, CHORDC1, HSPB7, and GAA) was independently and successfully substantiated by Western blotting. We observed that treating NPC1(I1061T) cells with four classes of seven different compounds that are potential NPC drugs increased the expression level of SOD2 and DHCR24. We have also shown an abnormal accumulation of glycogen in NPC1(I1061T) fibroblasts possibly triggered by defective processing of lysosomal alpha-glucosidase. Our study provides a starting point for future more focused investigations to better understand the mechanisms by which the reported dysregulated proteins triggers the pathological cascade in NPC, and furthermore, their effect upon therapeutic interventions.Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis.Rauniyar Navin N,Subramanian Kanagaraj K,Lavallée-Adam Mathieu M,Martínez-Bartolomé Salvador S,Balch William E WE,Yates John R JR 3rd,Rauniyar Navin N,Subramanian Kanagaraj K,Lavallée-Adam Mathieu M,Martínez-Bartolomé Salvador S,Balch William E WE,Yates John R JR,Rauniyar Navin N, Subramanian Kanagaraj K, Lavallée-Adam Mathieu M, Martínez-Bartolomé Salvador S, Balch William E WE, Yates John R JRPICK, human disease, Homo sapients, human being, DMDA1, number, Humo sapiens, A4, PRKCABP, Homo sapiense, man, Homo sapines, presence, human, TYPE, LGMD2C, DAGA4, count in organism, Homo spaiens, Homo spiens, "human" EXACT genbank_common_name [], DMDA, Homo sapien, count, Homo sapience, Homo sapian, Homo sampiens, Diseases., Homo sapians, SCARMD2, Homo sapiens disease, virulence, quantitative, Homo sapeins, MAM, Home sapiens, SCG3, Fibroblast, presence or absence in organismprojections, biochemical pathways, APR, Metabolic Process, Plays, Gene Ontology Projects, determination, mol, lamellae, Processes, Metabolisms, caspase-dependent programmed cell death, number, Metabolic Concepts, A4, APOER, Gene, Bioenergetics, Metabolic Processes, apoptotic programmed cell death, type I programmed cell death, presence, process of organ, TYPE, Gene Ontology Project, activation of apoptosis, Gene Ontology, protrusion, DAGA4, lamella, CD91, Extrinsic Pathway Apoptoses, GM18453, Metabolism, Gene Products, Project, Concepts, Expenditure, Metabolism Concept, Type I, MAM, Phenomenon, SCG3, Metabolism Phenomena, Reactive, Toy, study, Playthings, cell, catabolism, NOXA, Energy, Metabolic Concept, labeling, proteins, metabolic process resulting in cell growth, ridges, Expenditures, apoptosis activator activity, Oxygen Species, GM05659., Oxygen, Intrinsic Pathway Apoptosis, Puppets, A2MR, papilla, execution phase of apoptotic process, LRP1A, Play, biotransformation, laminae, Active Oxygen, programmed cell death by apoptosis, Catabolism, thiol methyltransferase activity, Puppet, Apoptosis, lipid localisation, incorporation, cellular suicide, data, Pro Oxidants, anatomical protrusion, cell suicide, degradation, Process, LRP, anatomical process, metabolism resulting in cell growth, Proteins, apoptotic cell death, lamina, flanges, Cell, LGMD2C, Concept, Metabolic Phenomena, polypeptide, Metabolism Concepts, count in organism, S-adenosyl-L-methionine:thiol S-methyltransferase activity, Experiment, signaling (initiator) caspase activity, count, induction of apoptosis, Playthings and Play, Intrinsic Pathway, Programmed Cell Death, Extrinsic Pathway Apoptosis, chemical analysis, Protein, shelf, Phenomena, Plaything, TGFBR5, Active, Ontology Projects, steroid metabolism, NPC1, metabolism, Oxygen Radicals, flange, organ process, Metabolic Phenomenon, Energy Expenditure, NPC, Ontology Project, apoptosis signaling, Gene Ontologies, Ontology, mobilization, multicellular organism metabolic process, Ontologies, DMDA1, Projects, biodegradation, apoptosis, Metabolic, shelves, Toys, Energy Expenditures, projection, ridge, turnover, Bioenergetic, Protein Gene Products, Intrinsic Pathway Apoptoses, Gene Proteins, process, processes, Energy Metabolisms, single-organism metabolic process, DMDA, induction of apoptosis by p53, spine, apoptotic program, SCARMD2, Pro-Oxidants, Extrinsic Pathway, commitment to apoptosis, processus, assay, quantitative, TMT, Proteomes, Apoptoses, IGFBP3R, Fibroblast, presence or absence in organism, AnabolismNPC, PICK, human disease, Homo sapients, human being, number, Humo sapiens, PRKCABP, proteins, Homo sapiense, man, Homo sapines, presence, human, Mutations, polypeptide, count in organism, Homo spaiens, Homo spiens, "human" EXACT genbank_common_name [], Homo sapien, count, Homo sapience, Homo sapian, Homo sampiens, Homo sapians, Diseases, Homo sapiens disease, NPC1, virulence., quantitative, Homo sapeins, Home sapiens, Fibroblast, presence or absence in organismprojections, biochemical pathways, nuclear pore membrane protein, PICK, Metabolic Process, Gene Ontology Projects, determination, 23-, Metabolisms, rad/s^[2], Metabolic Concepts, A4, Bioenergetics, type I programmed cell death, Mutations, 24+, Extrinsic Pathway Apoptoses, C27H46O, Project, Concepts, Mouse Neural Progenitor cell line., Expenditure, Metabolism Concept, nucleopore, Phenomenon, Missense, Cytochrome P450 8B1, increased, human disease, 21-25, MNSOD, nuclear pore complex, 25+, AA409036, catabolism, LYAG, Missense Mutations, Cholest-5-en-3beta-ol, proteins, metabolic process resulting in cell growth, Epicholesterol, 6-8, Oxygen, Intrinsic Pathway Apoptosis, 26+, medicine, papilla, Cardiovascular heat shock protein, Allele, biotransformation, Hsp25-2, Homo sapiens disease, MnSOD, Catabolism, 7 Alpha-Hydroxy-4-Cholesten-3-One 12-Alpha-Hydroxylase, lipid localisation, incorporation, cellular suicide, anatomical protrusion, Heat shock protein 25 kDa 2, Steroid 12-Alpha-Hydroxylase, Process, aberrant, functional failure, Chp-1, metabolism resulting in cell growth, lamina, flanges, late, InChIKey=HVYWMOMLDIMFJA-DPAQBDIFBB, signaling (initiator) caspase activity, count, induction of apoptosis, Playthings and Play, Intrinsic Pathway, Extrinsic Pathway Apoptosis, Diseases, shelf, Plaything, Ontology Projects, 1-5H3/t19-, failure, InChI=1/C27H46O/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28)13-15-26(20, Oxygen Radicals, NPC, 28H, Gene Ontologies, Ontology, Ontologies, Projects, shelves, Toys, pooled, alpha, projection, ridge, turnover, Intrinsic Pathway Apoptoses, A830007P12Rik, E430018M07Rik, Cytochrome P450 Subfamily VIIIB (Sterol 12-Alpha-Hydroxylase) Polypeptide 1, Energy Metabolisms, DMDA, 4)25(22)14-16-27(23, induction of apoptosis by p53, Patient, spine, CYP8B1, Extrinsic Pathway, 10-17H2, RGD1308019, morgana, Proteomes, Apoptoses, cvHsp, cvHSP, Fibroblast, accessory, CLG, atypia, Allelomorphs, Cln, Plays, lamellae, Processes, CLGN, caspase-dependent programmed cell death, number, Gene, PRKCABP, IPOB, disfunctional, Metabolic Processes, CHP1, apoptotic programmed cell death, presence, process of organ, supernumerary, TYPE, Gene Ontology Project, activation of apoptosis, Gene Ontology, protrusion, DAGA4, lamella, 4930459O04Rik, 1110001O09Rik, Missense Mutation, Cholest-5-en-3-ol (3beta)-, Metabolism, Gene Products, atypical, Type I, MAM, 27kDa, SCG3, Metabolism Phenomena, Cytochrome P450 Family 8 Subfamily B Polypeptide 1, Reactive, Toy, 18-19, study, Sterol 12 Alpha Hydroxylase, Playthings, Energy, Metabolic Concept, labeling, ridges, Expenditures, apoptosis activator activity, Oxygen Species, Allelomorph, Protein p19|6.8, drugs, Puppets, Clients, execution phase of apoptotic process, Mouse Neural Progenitor cell line, Play, laminae, Active Oxygen, programmed cell death by apoptosis, Puppet, AI528775, Apoptosis, data, Pro Oxidants, cell suicide, degradation, anatomical process, Proteins, apoptotic cell death, CYPVIIIB1, defective, 24)5/h9, Client, Cell, LGMD2C, Concept, Metabolic Phenomena, polypeptide, Metabolism Concepts, count in organism, Glucosidase, Programmed Cell Death, chemical analysis, Protein, Phenomena, Cytochrome P450 CYP8B1, Active, NPC1, steroid metabolism, Cholesterin, HspB7, metabolism, flange, organ process, Metabolic Phenomenon, Energy Expenditure, Ontology Project, apoptosis signaling, mobilization, multicellular organism metabolic process, Sod-2, DMDA1, biodegradation, apoptosis, MVCD6, mating_type_alpha, Metabolic, 21+, increased number, Energy Expenditures, C9orf167, Bioenergetic, Protein Gene Products, Gene Proteins, process, processes, present in greater numbers in organism, 27-/m1/s1, single-organism metabolic process, 22+, apoptotic program, SCARMD2, Pro-Oxidants, alpha mating type (yeast), commitment to apoptosis, processus, assay, [H][C@@]1(CC[C@@]2([H])[C@]3([H])CC=C4C[C@@H](O)CC[C@]4(C)[C@@]3([H])CC[C@]12C)[C@H](C)CCCC(C)C, quantitative, presence or absence in organism, Anabolism4905http://gpmdb.thegpm.org/~/dblist_gpmnum/gpmnum=GPM32320014822dbgap_ncbi~0patentfamilies~0rfam~0merops~0complex-portal~0uniprot~0wormbaseparasite~0embl-covid19~0reactome~0emdb~0wgs_masters~0ebiweb_resources~0opentargets_genetics~0biomodels_all~0ipd-mhc~0ebiweb_teams~0taxonomy~0genome_assembly~0sc-experiments~0ebiweb_people~0enzymeportal_enzymes~0ipd-nhkir~0cellosaurus~0pdbe~0chebi~0patentproteins~0interpro7~0uniref~0chembl~0pdbekb~0gpcrdb~0hgnc~0sc-genes~0intact~0rhea~0ebiweb_training~0alphafold~0imgt-hla~0patentnucleotides~0ensemblroot~0eva_studies~0non-coding~0europepmc~0pubmed~1identifiers_registry~0pdbechem~0hpa-covid19~0eva-variants-covid19~0biosamples~0gwas_catalog~0biotools~0tls_masters~0mesh~0coding~0sra~0opentargets~0efo~0embl-pathogen~0project~0pride~1human_diseases~0geo_datasets~0embl~0treefam~0uniparc~0ols~0dgva~0intenz~0go~0tsa_masters~0biosamples-covid19~0ebiweb_corporate~0omim~0lrg~0earlycause-molecular-sequences~0ipd-kir~0empiar~0rnacentral~0orcid_data_claims~0gpmdb~2lineage-covid19~0metagenomics~0pfam~0pride archive~1varsite~00Resource Reanalysis0.00.00.0151141270820481180.01.0falseQuantitative proteomics of human NPC1I1061T (sic) mutant fibroblasts provides insights into the pathogenesis of Niemann-Pick Type C disease.Data from ProteomeXchange, PXD ID: PXD001938. Experiment: WTvsI1061T_TMT_inj01, file: folder summary. Published as part of Mol Cell Proteomics. 2015 Apr 14 . From the Abstract: {{i}} In our study, an isobaric labeling based quantitative analysis of proteome of NPC1I1061T (sic) primary fibroblasts when compared to wild-type cells identified 281 differentially expressed proteins based on stringent data analysis criteria. Gene ontology enrichment analysis revealed that these proteins play important roles in diverse cellular processes such as protein maturation, energy metabolism, metabolism of reactive oxygen species, antioxidant activity, steroid metabolism, lipid localization, and apoptosis. {{/i}} Cell types: GM18453 (NPC1:p.I1061T) and GM05659 (wt).2015-04-22GPM3232001482225873482PXD001938PXD001938