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https://www.readbyqxmd.com/read/28105569/the-spectrum-of-niemann-pick-type-c-disease-in-greece
#1
Irene Mavridou, Evangelia Dimitriou, Marie T Vanier, Lluisa Vilageliu, Daniel Grinberg, Philippe Latour, Athina Xaidara, Lilia Lycopoulou, Sevasti Bostantjopoulou, Dimitrios Zafeiriou, Helen Michelakakis
Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years...
January 20, 2017: JIMD Reports
https://www.readbyqxmd.com/read/28102838/autophagy-dysregulation-in-danon-disease
#2
Anna Chiara Nascimbeni, Marina Fanin, Corrado Angelini, Marco Sandri
The autophagy-lysosome system is critical for muscle homeostasis and defects in lysosomal function result in a number of inherited muscle diseases, generally referred to as autophagic vacuolar myopathies (AVMs). Among them, Danon Disease (DD) and glycogen storage disease type II (GSDII) are due to primary lysosomal protein defects. DD is characterized by mutations in the lysosome-associated membrane protein 2 (LAMP2) gene. The DD mouse model suggests that inefficient lysosome biogenesis/maturation and impairment of autophagosome-lysosome fusion contribute to the pathogenesis of muscle wasting...
January 19, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28094782/cocaine-enhances-dc-to-t-cell-hiv-1-transmission-by-activating-dc-sign-larg-lsp1-complex-and-facilitating-infectious-synapse-formation
#3
Anil Prasad, Rutuja Kulkarni, Shuxian Jiang, Jerome E Groopman
DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated 'signalosome' complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs...
January 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28090783/probing-the-druggability-of-membrane-bound-rab5-by-molecular-dynamics-simulations
#4
Eileen Edler, Matthias Stein
Rab5 is a small GTPase and a key regulator in early endosomal trafficking. Rab5 and its effectors are involved in a large number of infectious diseases and certain types of cancer. We performed µs atomistic molecular dynamics simulations of inactive and active full-length Rab5 anchored to a complex model bilayer with composition of the early endosome membrane. Direct interactions between the Rab5 G domain and the bilayer were observed. We found two dominant nucleotide-dependent orientations characterised by a different accessibility of the switch regions...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28077878/pla2g16-represents-a-switch-between-entry-and-clearance-of-picornaviridae
#5
Jacqueline Staring, Eleonore von Castelmur, Vincent A Blomen, Lisa G van den Hengel, Markus Brockmann, Jim Baggen, Hendrik Jan Thibaut, Joppe Nieuwenhuis, Hans Janssen, Frank J M van Kuppeveld, Anastassis Perrakis, Jan E Carette, Thijn R Brummelkamp
Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non-enveloped viruses, their biology has been extensively studied. Although a range of different cell-surface receptors are bound by different picornaviruses, it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8, 9, 10, 11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle...
January 19, 2017: Nature
https://www.readbyqxmd.com/read/28077646/adenovirus-modulates-toll-like-receptor-4-signaling-by-reprogramming-orp1l-vap-protein-contacts-for-cholesterol-transport-from-endosomes-to-the-endoplasmic-reticulum
#6
Nicholas L Cianciola, Stacey Chung, Danny Manor, Cathleen R Carlin
: Human adenoviruses generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RIDα via its direct interaction with the sterol-binding protein ORP1L. Second, determine how this interaction regulates innate immunity to adenovirus...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28071667/photogate-microscopy-to-track-single-molecules-in-crowded-environments
#7
Vladislav Belyy, Sheng-Min Shih, Jigar Bandaria, Yongjian Huang, Rosalie E Lawrence, Roberto Zoncu, Ahmet Yildiz
Tracking single molecules inside cells reveals the dynamics of biological processes, including receptor trafficking, signalling and cargo transport. However, individual molecules often cannot be resolved inside cells due to their high density. Here we develop the PhotoGate technique that controls the number of fluorescent particles in a region of interest by repeatedly photobleaching its boundary. PhotoGate bypasses the requirement of photoactivation to track single particles at surface densities two orders of magnitude greater than the single-molecule detection limit...
January 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28069747/a-targeted-rnai-screen-identifies-factors-affecting-diverse-stages-of-receptor-mediated-transcytosis
#8
Bradlee Nelms, Natasha Furtado Dalomba, Wayne Lencer
Endosome transport by transcytosis is the primary mechanism by which proteins and other large cargo traverse epithelial barriers in normal tissue. Transcytosis is also essential for establishing and maintaining membrane polarity in epithelia and other polarized cells. To identify novel components of this pathway, we conducted a high-throughput RNA interference screen for factors necessary for the bidirectional transcytosis of IgG by the Fcγ receptor FcRn. This screen identified 23 genes whose suppression resulted in a reproducible decrease in FcRn-mediated transcytosis...
January 9, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28066811/ph-dependent-cellular-internalization-of-paramagnetic-nanoparticle
#9
Branislava Janic, Mohammed Pi Bhuiyan, James R Ewing, Meser M Ali
A hallmark of the tumor microenvironment in malignant tumor is extracellular acidosis, which can be exploited for targeted delivery of drugs and imaging agents. A pH sensitive paramagnetic nanoaparticle (NP) is developed by incorporating GdDOTA-4AmP MRI contrast agent and pHLIP (pH Low Insertion Peptide) into the surface of a G5-PAMAM dendrimer. pHLIP showed pH-selective insertion and folding into cell membranes, but only in acidic conditions. We demonstrated that pHLIP-conjugated Gd44-G5 paramagnetic nanoparticle binds and fuses with cellular membrane at low pH, but not at normal physiological pH, and that it promotes cellular uptake...
August 26, 2016: ACS Sensors
https://www.readbyqxmd.com/read/28065471/mutations-in-atp6v1e1-or-atp6v1a-cause-autosomal-recessive-cutis-laxa
#10
Tim Van Damme, Thatjana Gardeitchik, Miski Mohamed, Sergio Guerrero-Castillo, Peter Freisinger, Brecht Guillemyn, Ariana Kariminejad, Daisy Dalloyaux, Sanne van Kraaij, Dirk J Lefeber, Delfien Syx, Wouter Steyaert, Riet De Rycke, Alexander Hoischen, Erik-Jan Kamsteeg, Sunnie Y Wong, Monique van Scherpenzeel, Payman Jamali, Ulrich Brandt, Leo Nijtmans, G Christoph Korenke, Brian H Y Chung, Christopher C Y Mak, Ingrid Hausser, Uwe Kornak, Björn Fischer-Zirnsak, Tim M Strom, Thomas Meitinger, Yasemin Alanay, Gulen E Utine, Peter K C Leung, Siavash Ghaderi-Sohi, Paul Coucke, Sofie Symoens, Anne De Paepe, Christian Thiel, Tobias B Haack, Fransiska Malfait, Eva Morava, Bert Callewaert, Ron A Wevers
Defects of the V-type proton (H(+)) ATPase (V-ATPase) impair acidification and intracellular trafficking of membrane-enclosed compartments, including secretory granules, endosomes, and lysosomes. Whole-exome sequencing in five families affected by mild to severe cutis laxa, dysmorphic facial features, and cardiopulmonary involvement identified biallelic missense mutations in ATP6V1E1 and ATP6V1A, which encode the E1 and A subunits, respectively, of the V1 domain of the heteromultimeric V-ATPase complex. Structural modeling indicated that all substitutions affect critical residues and inter- or intrasubunit interactions...
December 29, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28062852/a-proteomic-approach-to-identify-endosomal-cargoes-controlling-cancer-invasiveness
#11
Jesica Diaz-Vera, Sarah Palmer, Juan Ramon Hernandez-Fernaud, Emmanuel Dornier, Louise E Mitchell, Iain Macpherson, Joanne Edwards, Sara Zanivan, Jim C Norman
We have previously shown that Rab17 - a small GTPase associated with epithelial polarity - is specifically suppressed by ERK2 signalling to promote an invasive phenotype. However, the mechanisms through which Rab17 loss permits invasiveness, and the endosomal cargoes that are responsible for mediating this are not known. Using quantitative mass spectrometry-based proteomics, we have found that knockdown of Rab17 leads to highly selective reduction in the cellular levels of a v-SNARE (Vamp8). Moreover, proteomics and immunofluorescence indicate that Vamp-8 is associated with Rab17 at late endosomes...
January 6, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/28060560/harnessing-membrane-trafficking-to-promote-cancer-spreading-and-invasion-the-case-of-rab2a
#12
Hiroaki Kajiho, Yuko Kajiho, Giorgio Scita
How cancer disseminates and metastasizes remains an outstanding open question. Emerging evidence indicates that membrane trafficking is frequently harnessed by tumours of epithelial origin to acquire a mesenchymal program of invasiveness. However, the critical molecular hubs utilized by cancer cells this context have only began to be elucidated. Here, we discussed the results of a recent phenotypic screening that led to the identification of the small GTPase RAB2A, not previously involved in cancer dissemination, as pivotal for the acquisition of pericellular proteolysis, cell dissemination and distant metastatic spreading of human breast cancer...
January 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/28057802/cfs1p-a-novel-membrane-protein-in-the-pq-loop-family-is-involved-in-phospholipid-flippase-functions-in-yeast
#13
Takaharu Yamamoto, Konomi Fujimura-Kamada, Eno Shioji, Risa Suzuki, Kazuma Tanaka
Type 4 P-type ATPases (P4-ATPases) function as phospholipid flippases, which translocate phospholipids from the exoplasmic leaflet to the cytoplasmic leaflet of the lipid bilayer, to generate and maintain asymmetric distribution of phospholipids at the plasma membrane and endosomal/Golgi membranes. The budding yeast Saccharomyces cerevisiae has four heteromeric flippases (Drs2p, Dnf1p, Dnf2p, and Dnf3p), associated with the Cdc50p family noncatalytic subunit, and one monomeric flippase, Neo1p They have been suggested to function in vesicle formation in membrane trafficking pathways, but details of their mechanisms remain to be clarified...
January 5, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28056926/edible-bird-s-nest-modulate-intracellular-molecular-pathways-of-influenza-a-virus-infected-cells
#14
Amin Haghani, Parvaneh Mehrbod, Nikoo Safi, Fadzilah A'ini Abd Kadir, Abdul Rahman Omar, Aini Ideris
BACKGROUND: Edible Bird's Nest (EBN) as a popular traditional Chinese medicine is believed to have health enhancing and antiviral activities against influenza A virus (IAV); however, the molecular mechanism behind therapeutic effects of EBN is not well characterized. METHODS: In this study, EBNs that underwent different enzymatic preparation were tested against IAV infected cells. 50% cytotoxic concentration (CC50) and 50% inhibitory concentration (IC50) of the EBNs against IAV strain A/Puerto Rico/8/1934(H1N1) were determined by HA and MTT assays...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28051077/fig4-variants-in-central-european-patients-with-amyotrophic-lateral-sclerosis-a-whole-exome-and-targeted-sequencing-study
#15
Alma Osmanovic, Isolde Rangnau, Anne Kosfeld, Susanne Abdulla, Claas Janssen, Bernd Auber, Peter Raab, Matthias Preller, Susanne Petri, Ruthild G Weber
We aimed to identify the genetic cause of the devastating neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a German family with two affected individuals, and to assess the prevalence of variants in the identified risk gene, FIG4, in a central European ALS cohort. Whole-exome sequencing (WES) and an overlapping data analysis strategy were performed in an ALS family with autosomal dominant inheritance and incomplete penetrance. Additionally, 200 central European ALS patients were analyzed using whole-exome or targeted sequencing...
January 4, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28049734/sphingosine-and-sphingosine-kinase-1-involvement-in-endocytic-membrane-trafficking
#16
Santiago Lima, Sheldon Milstien, Sarah Spiegel
The balance between cholesterol and sphingolipids within the plasma membrane has long been implicated in endocytic membrane trafficking. However, in contrast to cholesterol functions, little is still known about the roles of sphingolipids and their metabolites. Perturbing the cholesterol/sphingomyelin balance was shown to induce narrow tubular plasma membrane invaginations enriched with sphingosine kinase 1 (SphK1), the enzyme that converts the bioactive sphingolipid metabolite sphingosine to sphingosine-1-phosphate (S1P), and suggested a role for sphingosine phosphorylation in endocytic membrane trafficking...
January 3, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28043862/rapid-and-facile-quantitation-of-polyplex-endocytic-trafficking
#17
Mihael Lazebnik, Daniel W Pack
Design of safe and effective synthetic nucleic acid delivery vectors such as polycation/DNA or polycation/siRNA complexes (polyplexes) will be facilitated by quantitative understanding of the mechanisms by which such materials escort cargo from the cell surface to the nucleus. In particular, the mechanisms of cellular internalization by various endocytosis pathways and subsequent endocytic vesicle trafficking have been shown to strongly affect nucleic acid delivery efficiency. Fluorescence microscopy and subcellular fractionation methods are commonly employed to follow intracellular trafficking of biomolecules and nanoparticulate delivery systems such as polyplexes...
December 31, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28040639/poly-amidoamine-dendrimers-with-a-precisely-core-positioned-sulforhodamine-b-molecule-for-comparative-biological-tracing-and-profiling
#18
Lin-Ping Wu, Mario Ficker, Søren L Mejlsøe, Arnaldur Hall, Valentina Paolucci, Jørn B Christensen, Panagiotis N Trohopoulos, Seyed M Moghimi
We report on a simple robust procedure for synthesis of generation-4 poly-(amidoamine) (PAMAM) dendrimers with a precisely core positioned single sulforhodamine B molecule. The labelled dendrimers exhibited high fluorescent quantum yields where the absorbance and fluorescence spectrum of the fluorophore was not affected by pH and temperature. Since the stoichiometry of the fluorophore to the dendrimer is 1:1, we were able to directly compare uptake kinetics, the mode of uptake, trafficking and safety of dendrimers of different end-terminal functionality (carboxylated vs...
December 29, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28040547/lemur-tyrosine-kinase-2-lmtk2-is-a-determinant-of-cell-sensitivity-to-apoptosis-by-regulating-the-levels-of-the-bcl2-family-members
#19
Annalisa Conti, Maria Teresa Majorini, Enrico Fontanella, Alberto Bardelli, Mauro Giacca, Domenico Delia, Miguel Mano, Daniele Lecis
Using a high-throughput approach, we identified lemur tyrosine kinase 2 (LMTK2) as a novel determinant of cell sensitivity to TRAIL. LMTK2 is a poorly characterized serine/threonine kinase believed to play a role in endosomal membrane trafficking and neuronal physiology, and recently found to be mutated in diverse tumor types. We show that LMTK2 silencing sensitizes immortalized epithelial cells and cancer cells to TRAIL, and this phenomenon is accompanied by changes in the expression of BCL2 family members...
December 29, 2016: Cancer Letters
https://www.readbyqxmd.com/read/28039431/data-integration-in-physiology-using-bayes-rule-and-minimum-bayes-factors-deubiquitylating-enzymes-in-the-renal-collecting-duct
#20
Zhe Xue, Jia-Xu Chen, Yue Zhao, Barbara Medvar, Mark A Knepper
A major challenge in physiology is to exploit the many large-scale datasets available from "-omic" studies in order to seek answers to key physiological questions. In previous studies, Bayes' Theorem has been used for this purpose. This approach requires a means to map continuously distributed experimental data to probabilities (likelihood values) in order to derive posterior probabilities from the combination of prior probabilities and new data. Here, we introduce the use of Minimum Bayes' Factors for this purpose and illustrate the approach by addressing a physiological question, "Which deubiquitylating enzymes (DUBs) encoded by mammalian genomes are most likely to regulate plasma membrane transport processes in renal cortical collecting duct principal cells?" To do this, we have created a comprehensive online database of 110 DUBs present in the mammalian genome (https://hpcwebapps...
December 30, 2016: Physiological Genomics
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