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Bis(monoacylglycero)phosphate lipids in the retinal pigment epithelium implicate lysosomal/endosomal dysfunction in a model of Stargardt disease and human retinas.
Anderson DMG, Ablonczy Z, Koutalos Y, Hanneken AM, Spraggins JM, Calcutt MW, Crouch RK, Caprioli RM, Schey KL
(2017) Sci Rep 7: 17352
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Disease Models, Animal, Endosomes, Humans, Lipids, Lysophospholipids, Lysosomes, Macular Degeneration, Mice, Mice, Knockout, Monoglycerides, Retina, Retinal Pigment Epithelium
Show Abstract · Added March 22, 2018
Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4 Stargardt model mice compared to their relevant background strain. Extensive analysis by LC-MS/MS in both positive and negative ion mode was required to accurately confirm the identity of one highly expressed lipid class, bis(monoacylgylercoro)phosphate (BMP) lipids, and to distinguish them from isobaric species. The same BMP lipids were also detected in the RPE of healthy human retina. BMP lipids have been previously associated with the endosomal/lysosomal storage diseases Niemann-Pick and neuronal ceroid lipofuscinosis and have been reported to regulate cholesterol levels in endosomes. These results suggest that perturbations in lipid metabolism associated with late endosomal/lysosomal dysfunction may play a role in the pathogenesis of Stargardt disease and is evidenced in human retinas.
0 Communities
3 Members
0 Resources
14 MeSH Terms
Directed evolution of a sphingomyelin flippase reveals mechanism of substrate backbone discrimination by a P4-ATPase.
Roland BP, Graham TR
(2016) Proc Natl Acad Sci U S A 113: E4460-6
MeSH Terms: ATP-Binding Cassette Transporters, Adenosine Triphosphatases, Amino Acid Sequence, Asparagine, Biological Transport, Cell Membrane, Directed Molecular Evolution, Gain of Function Mutation, Mutagenesis, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Homology, Amino Acid, Sphingomyelins, Substrate Specificity
Show Abstract · Added April 6, 2017
Phospholipid flippases in the type IV P-type ATPase (P4-ATPases) family establish membrane asymmetry and play critical roles in vesicular transport, cell polarity, signal transduction, and neurologic development. All characterized P4-ATPases flip glycerophospholipids across the bilayer to the cytosolic leaflet of the membrane, but how these enzymes distinguish glycerophospholipids from sphingolipids is not known. We used a directed evolution approach to examine the molecular mechanisms through which P4-ATPases discriminate substrate backbone. A mutagenesis screen in the yeast Saccharomyces cerevisiae has identified several gain-of-function mutations in the P4-ATPase Dnf1 that facilitate the transport of a novel lipid substrate, sphingomyelin. We found that a highly conserved asparagine (N220) in the first transmembrane segment is a key enforcer of glycerophospholipid selection, and specific substitutions at this site allow transport of sphingomyelin.
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1 Members
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14 MeSH Terms
Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.
Hohman TJ, Cooke-Bailey JN, Reitz C, Jun G, Naj A, Beecham GW, Liu Z, Carney RM, Vance JM, Cuccaro ML, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF, Larson EB, Graff-Radford NR, Evans D, De Jager PL, Crane PK, Buxbaum JD, Murrell JR, Raj T, Ertekin-Taner N, Logue MW, Baldwin CT, Green RC, Barnes LL, Cantwell LB, Fallin MD, Go RC, Griffith P, Obisesan TO, Manly JJ, Lunetta KL, Kamboh MI, Lopez OL, Bennett DA, Hardy J, Hendrie HC, Hall KS, Goate AM, Lang R, Byrd GS, Kukull WA, Foroud TM, Farrer LA, Martin ER, Pericak-Vance MA, Schellenberg GD, Mayeux R, Haines JL, Thornton-Wells TA, Alzheimer Disease Genetics Consortium
(2016) Alzheimers Dement 12: 233-43
MeSH Terms: ATP-Binding Cassette Transporters, African Americans, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Chi-Square Distribution, Chromosome Aberrations, Cohort Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Sialic Acid Binding Ig-like Lectin 3
Show Abstract · Added April 10, 2018
INTRODUCTION - African-American (AA) individuals have a higher risk for late-onset Alzheimer's disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome-wide association study in AAs to date confirmed that six of the Alzheimer's disease (AD)-related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.
METHODS - We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status.
RESULTS - Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences.
DISCUSSION - Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.
Copyright © 2016 The Alzheimer's Association. All rights reserved.
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1 Members
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MeSH Terms
Bisphosphonates: from softening water to treating PXE.
Moore SN, Tanner SB, Schoenecker JG
(2015) Cell Cycle 14: 1354-5
MeSH Terms: ATP-Binding Cassette Transporters, Alendronate, Animals, Bone Density Conservation Agents, Etidronic Acid, Female, Humans, Male, Pseudoxanthoma Elasticum, Vascular Calcification
Added February 22, 2016
0 Communities
1 Members
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10 MeSH Terms
ABCG5/G8 deficiency in mice reduces dietary triacylglycerol and cholesterol transport into the lymph.
Zhang LS, Xu M, Yang Q, Lou D, Howles PN, Tso P
(2015) Lipids 50: 371-9
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 5, ATP Binding Cassette Transporter, Subfamily G, Member 8, ATP-Binding Cassette Transporters, Animals, Biological Transport, Body Composition, Cholesterol, Dietary Fats, Gene Knockout Techniques, Intestine, Small, Lipoproteins, Lymph, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Triglycerides
Show Abstract · Added August 24, 2015
The adenosine triphosphate-binding cassette (ABC) transporter G5/G8 is critical in protecting the body from accumulating dietary plant sterols. Expressed in the liver and small intestine, it transports plant sterols into the biliary and intestinal lumens, thus promoting their excretion. The extent to which G5/G8 regulates cholesterol absorption remains unclear. G5/G8 is also implicated in reducing the absorption of dietary triacylglycerols (TAG) by unknown mechanisms. We hypothesized that G5/G8 suppresses the production of chylomicrons, and its deficiency would enhance the absorption of both dietary TAG and cholesterol. The aim of this study was to investigate the effects of G5/G8 deficiency on lipid uptake and secretion into the lymph under steady-state conditions. Surprisingly, compared with wild-type mice (WT) (n = 9), G5/G8 KO (n = 13) lymph fistula mice given a continuous intraduodenal infusion of [3H]-TAG and [14C]-cholesterol showed a significant (P < 0.05) reduction in lymphatic transport of both [(3)H]-TAG and [(14)C]-cholesterol, concomitant with a significant (P < 0.05) increase of [(3)H]-TAG and [(14)C]-cholesterol accumulated in the intestinal lumen. There was no difference in the total amount of radiolabeled lipids retained in the intestinal mucosa between the two groups. G5/G8 KO mice given a bolus of TAG showed reduced intestinal TAG secretion compared with WT, suggesting an independent role for G5/G8 in facilitating intestinal TAG transport. Our data demonstrate that G5/G8 deficiency reduces the uptake and secretion of both dietary TAG and cholesterol by the intestine, suggesting a novel role for the sterol transporter in the formation and secretion of chylomicrons.
0 Communities
1 Members
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17 MeSH Terms
A non-BRICHOS SFTPC mutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy.
Hawkins A, Guttentag SH, Deterding R, Funkhouser WK, Goralski JL, Chatterjee S, Mulugeta S, Beers MF
(2015) Am J Physiol Lung Cell Mol Physiol 308: L33-47
MeSH Terms: ATP-Binding Cassette Transporters, Adaptor Proteins, Signal Transducing, Amino Acid Substitution, Autophagy, Autophagy-Related Protein 8 Family, Female, Gene Expression Regulation, Genetic Diseases, Inborn, HEK293 Cells, Humans, Infant, Lung Diseases, Interstitial, Lysosomes, Membrane Potential, Mitochondrial, Microfilament Proteins, Microtubule-Associated Proteins, Mitochondria, Mutation, Missense, Proteostasis Deficiencies, Pulmonary Surfactant-Associated Protein C, Sequestosome-1 Protein, Ubiquitin-Protein Ligases, Vacuoles, rab GTP-Binding Proteins
Show Abstract · Added January 20, 2015
Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene (SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-C(I73T) within the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-C(WT)) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-C(I73T) was dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-C(I73T) exhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-C(I73T). By transmission electron microscopy, hSP-C(I73T) cells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-C(I73T) cells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-C(I73T) cells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-C(I73T) induces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD.
Copyright © 2015 the American Physiological Society.
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1 Members
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24 MeSH Terms
Coenzyme Q10 increases cholesterol efflux and inhibits atherosclerosis through microRNAs.
Allen RM, Vickers KC
(2014) Arterioscler Thromb Vasc Biol 34: 1795-7
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters, Animals, Atherosclerosis, Cholesterol, Humans, Lipoproteins, Macrophages, Male, MicroRNAs, Transcription Factor AP-1, Ubiquinone
Added February 12, 2016
0 Communities
1 Members
0 Resources
12 MeSH Terms
ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling.
Marriott S, Baskir RS, Gaskill C, Menon S, Carrier EJ, Williams J, Talati M, Helm K, Alford CE, Kropski JA, Loyd J, Wheeler L, Johnson J, Austin E, Nozik-Grayck E, Meyrick B, West JD, Klemm DJ, Majka SM
(2014) Am J Physiol Cell Physiol 307: C684-98
MeSH Terms: ATP Binding Cassette Transporter, Subfamily G, Member 2, ATP-Binding Cassette Transporters, Animals, Cells, Cultured, Humans, Lung, Mesenchymal Stem Cells, Mice, Myofibroblasts, Neoplasm Proteins, Pericytes, Pulmonary Fibrosis, Transforming Growth Factor beta1
Show Abstract · Added January 20, 2015
Genesis of myofibroblasts is obligatory for the development of pathology in many adult lung diseases. Adult lung tissue contains a population of perivascular ABCG2(pos) mesenchymal stem cells (MSC) that are precursors of myofibroblasts and distinct from NG2 pericytes. We hypothesized that these MSC participate in deleterious remodeling associated with pulmonary fibrosis (PF) and associated hypertension (PH). To test this hypothesis, resident lung MSC were quantified in lung samples from control subjects and PF patients. ABCG2(pos) cell numbers were decreased in human PF and interstitial lung disease compared with control samples. Genetic labeling of lung MSC in mice enabled determination of terminal lineage and localization of ABCG2 cells following intratracheal administration of bleomycin to elicit fibrotic lung injury. Fourteen days following bleomycin injury enhanced green fluorescent protein (eGFP)-labeled lung MSC-derived cells were increased in number and localized to interstitial areas of fibrotic and microvessel remodeling. Finally, gene expression analysis was evaluated to define the response of MSC to bleomycin injury in vivo using ABCG2(pos) MSC isolated during the inflammatory phase postinjury and in vitro bleomycin or transforming growth factor-β1 (TGF-β1)-treated cells. MSC responded to bleomycin treatment in vivo with a profibrotic gene program that was not recapitulated in vitro with bleomycin treatment. However, TGF-β1 treatment induced the appearance of a profibrotic myofibroblast phenotype in vitro. Additionally, when exposed to the profibrotic stimulus, TGF-β1, ABCG2, and NG2 pericytes demonstrated distinct responses. Our data highlight ABCG2(pos) lung MSC as a novel cell population that contributes to detrimental myofibroblast-mediated remodeling during PF.
Copyright © 2014 the American Physiological Society.
2 Communities
5 Members
0 Resources
13 MeSH Terms
Conformational dynamics of the nucleotide binding domains and the power stroke of a heterodimeric ABC transporter.
Mishra S, Verhalen B, Stein RA, Wen PC, Tajkhorshid E, Mchaourab HS
(2014) Elife 3: e02740
MeSH Terms: ATP-Binding Cassette Transporters, Adenosine Triphosphate, Carrier Proteins, Catalytic Domain, Cell Membrane, Cloning, Molecular, Gene Expression Regulation, Hydrolysis, Molecular Dynamics Simulation, Nanotechnology, Nucleotides, Protein Conformation, Protein Multimerization
Show Abstract · Added May 30, 2014
Multidrug ATP binding cassette (ABC) exporters are ubiquitous ABC transporters that extrude cytotoxic molecules across cell membranes. Despite recent progress in structure determination of these transporters, the conformational motion that transduces the energy of ATP hydrolysis to the work of substrate translocation remains undefined. Here, we have investigated the conformational cycle of BmrCD, a representative of the heterodimer family of ABC exporters that have an intrinsically impaired nucleotide binding site. We measured distances between pairs of spin labels monitoring the movement of the nucleotide binding (NBD) and transmembrane domains (TMD). The results expose previously unobserved structural intermediates of the NBDs arising from asymmetric configuration of catalytically inequivalent nucleotide binding sites. The two-state transition of the TMD, from an inward- to an outward-facing conformation, is driven exclusively by ATP hydrolysis. These findings provide direct evidence of divergence in the mechanism of ABC exporters.DOI: http://dx.doi.org/10.7554/eLife.02740.001.
Copyright © 2014, Mishra et al.
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2 Members
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13 MeSH Terms
High resolution MALDI imaging mass spectrometry of retinal tissue lipids.
Anderson DM, Ablonczy Z, Koutalos Y, Spraggins J, Crouch RK, Caprioli RM, Schey KL
(2014) J Am Soc Mass Spectrom 25: 1394-403
MeSH Terms: ATP-Binding Cassette Transporters, Animals, Cyclotrons, Diagnostic Imaging, Fourier Analysis, Lipids, Macular Degeneration, Mice, Inbred C57BL, Mice, Knockout, Models, Biological, Photoreceptor Cells, Vertebrate, Retina, Retinal Neurons, Retinal Pigment Epithelium, Retinoids, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Tandem Mass Spectrometry
Show Abstract · Added May 20, 2014
Matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) has the ability to provide an enormous amount of information on the abundances and spatial distributions of molecules within biological tissues. The rapid progress in the development of this technology significantly improves our ability to analyze smaller and smaller areas and features within tissues. The mammalian eye has evolved over millions of years to become an essential asset for survival, providing important sensory input of an organism's surroundings. The highly complex sensory retina of the eye is comprised of numerous cell types organized into specific layers with varying dimensions, the thinnest of which is the 10 μm retinal pigment epithelium (RPE). This single cell layer and the photoreceptor layer contain the complex biochemical machinery required to convert photons of light into electrical signals that are transported to the brain by axons of retinal ganglion cells. Diseases of the retina, including age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy, occur when the functions of these cells are interrupted by molecular processes that are not fully understood. In this report, we demonstrate the use of high spatial resolution MALDI IMS and FT-ICR tandem mass spectrometry in the Abca4(-/-) knockout mouse model of Stargardt disease, a juvenile onset form of macular degeneration. The spatial distributions and identity of lipid and retinoid metabolites are shown to be unique to specific retinal cell layers.
1 Communities
3 Members
0 Resources
17 MeSH Terms