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https://www.readbyqxmd.com/read/27932943/vacuolar-protein-sorting-genes-in-parkinson-s-disease-a-re-appraisal-of-mutations-detection-rate-and-neurobiology-of-disease
#1
REVIEW
Stefano Gambardella, Francesca Biagioni, Rosangela Ferese, Carla L Busceti, Alessandro Frati, Giuseppe Novelli, Stefano Ruggieri, Francesco Fornai
Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27930980/vitamin-d3-intake-as-regulator-of-insulin-degrading-enzyme-and-insulin-receptor-phosphorylation-in-diabetic-rats
#2
Mohamed Mahmoud Elseweidy, Rawia Sarhan Amin, Hebatallah Husseini Atteia, Maha Abdo Ali
Insulin-degrading enzyme (IDE, insulysin) is a rate-limiting enzyme in the insulin degradation process. It is an intracellular 110-kDa thiol zinc-metalloendopeptidase located in the cytosol, peroxisomes, endosomes and cell surface. IDE catalyzes degradation of several small proteins including insulin, amylin and β-amyloid protein. In addition, insulin clearance was expressed as a target in the treatment of type 2 diabetes given the role of hyperinsulinemia in the pathogenesis of insulin resistance. In this study, fourtyadult male Wistar albino rats were used, thirty rats received 20% fructose in drinking water (HFW) for six weeks to induce diabetes...
December 5, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27930836/hepatitis-c-virus-infection-propagates-through-interactions-between-syndecan-1-and-cd81-and-impacts-the-hepatocyte-glycocalyx
#3
Boyan Grigorov, Emma Reungoat, Alice Gentil Dit Maurin, Mihayl Varbanov, Julie Blaising, Maud Michelet, Rachel Manuel, Romain Parent, Birke Bartosch, Fabien Zoulim, Florence Ruggiero, Eve-Isabelle Pécheur
The hepatitis C virus (HCV) infects hepatocytes after binding to heparan sulfate proteoglycans (HSPG), in particular Syndecan-1, followed by recognition of the tetraspanin CD81 and other receptors. HSPGs are found in a specific microenvironment coating the hepatocyte surface called the glycocalyx, and are receptors for extracellular matrix proteins, cytokines, growth factors, lipoproteins and infectious agents. We investigated the mutual influence of HCV infection on the glycocalyx, and revealed new links between Syndecan-1 and CD81...
December 8, 2016: Cellular Microbiology
https://www.readbyqxmd.com/read/27929705/snapin-is-critical-for-lysosomal-acidification-and-autophagosome-maturation-in-macrophages
#4
Bo Shi, Qi-Quan Huang, Robert Birkett, Renee Doyle, Andrea Dorfleutner, Christian Stehlik, Congcong He, Richard M Pope
We previously observed that SNAPIN, which is an adaptor protein in the SNARE core complex, was highly expressed in rheumatoid arthritis synovial tissue macrophages, but its role in macrophages and autoimmunity is unknown. To identify SNAPIN's role in these cells, we employed siRNA to silence the expression of SNAPIN in primary human macrophages. Silencing SNAPIN resulted in swollen lysosomes with impaired CTSD (cathepsin D) activation, although total CTSD was not reduced. Neither endosome cargo delivery nor lysosomal fusion with endosomes or autophagosomes was inhibited following the forced silencing of SNAPIN...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27928003/lassa-virus-cell-entry-reveals-new-aspects-of-virus-host-cell-interaction
#5
Giulia Torriani, Clara Galan-Navarro, Stefan Kunz
Viral entry represents the first step of every viral infection and is a determinant for the host-range and disease potential of a virus. Here we review the latest developments on cell entry of the highly pathogenic Old World arenavirus Lassa, providing novel insights into the complex host cell interaction of this important human pathogen. We will cover new discoveries on the molecular mechanisms of receptor recognition, endocytosis, and the use of late endosomal entry factors.
December 7, 2016: Journal of Virology
https://www.readbyqxmd.com/read/27927957/the-proteome-of-bloc-1-genetic-defects-identifies-the-arp2-3-actin-polymerization-complex-to-function-downstream-of-the-schizophrenia-susceptibility-factor-dysbindin-at-the-synapse
#6
Avanti Gokhale, Cortnie Hartwig, Amanda H Freeman, Ravi Das, Stephanie A Zlatic, Rachel Vistein, Amelia Burch, Guillemette Carrot, Arielle F Lewis, Sheldon Nelms, Dion K Dickman, Manojkumar A Puthenveedu, Daniel N Cox, Victor Faundez
: Proteome modifications downstream of monogenic or polygenic disorders have the potential to uncover novel molecular mechanisms participating in pathogenesis and/or extragenic modification of phenotypic expression. We tested this idea by determining the proteome sensitive to genetic defects in a locus encoding dysbindin, a protein required for synapse biology and implicated in schizophrenia risk. We applied quantitative mass spectrometry to identify proteins expressed in neuronal cells the abundance of which was altered after downregulation of the schizophrenia susceptibility factor dysbindin (Bloc1s8) or two other dysbindin-interacting polypeptides, which assemble into the octameric biogenesis of lysosome-related organelles complex 1 (BLOC-1)...
December 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27927216/lrrk2-at-the-interface-of-autophagosomes-endosomes-and-lysosomes
#7
REVIEW
Dorien A Roosen, Mark R Cookson
Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson's disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches...
December 7, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27925633/shock-wave-enhances-angiogenesis-through-vegfr2-activation-and-recycling
#8
Tien-Hung Huang, Cheuk-Kwan Sun, Yi-Ling Chen, Ching-Jen Wang, Tsung-Cheng Yin, Mel S Lee, Hon-Kan Yip
Although low-energy shock wave (SW) is adopted to treat ischemic diseases because of its pro-angiogenic properties, the underlying mechanism remains unclear. This study aimed at testing whether SW-induced angiogenesis may be through endothelial vascular endothelial growth factor receptor 2 (VEGFR2) signaling and trafficking. Phosphorylation of VEGFR2-Akt-eNOS axis and production of nitric oxide (NO) were determined in human umbilical vein endothelial cells (HUVECs) treated with SW. Carotid artery in ob/ob mice was treated with SW before evaluation with sprouting assay...
December 6, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27923836/the-swi-snf-complex-protein-snr1-is-a-tumor-suppressor-in-drosophila-imaginal-tissues
#9
Gengqiang Xie, Hanqing Chen, Dongyu Jia, Zhiqiang Shu, William Hunt Palmer, Yi-Chun Huang, Xiankun Zeng, Steven X Hou, Renjie Jiao, Wu-Min Deng
Components of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in various human cancers, yet only SMARCB1/hSNF5, a core member of the SWI/SNF complex, is mutated in malignant rhabdoid tumors (MRT). How SMARCB1/hSNF5 functions differently from other members of the SWI/SNF complex remains unclear. Here we use Drosophila imaginal epithelial tissues to demonstrate that Snr1, the conserved homolog of human SMARCB1/hSNF5, prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling cascades...
December 6, 2016: Cancer Research
https://www.readbyqxmd.com/read/27923812/an-l-to-d-amino-acid-conversion-in-the-cell-penetrating-peptide-dftat-influences-proteolytic-stability-endocytic-uptake-and-endosomal-escape
#10
Kristina Najjar, Alfredo Erazo-Oliveras, Dakota J Brock, Ting-Yi Wang, Jean-Philippe Pellois
Cell-penetrating peptides (CPPs) are well established as delivery agents for otherwise cell-impermeable cargos. CPPs can also theoretically be used to modulate intracellular processes. However, their susceptibility to proteolytic degradation often limits their utility in these applications. Previous studies have explored the consequences on cellular uptake of converting the residues in CPPs from L to D stereochemistry, but conflicting results have been reported and specific steps en route to intracellular activity have not been explored...
December 6, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27923483/regulation-of-membrane-type-1-matrix-metalloproteinase-activity-and-intracellular-localization-in-clinical-thoracic-aortic-aneurysms
#11
John S Ikonomidis, Elizabeth K Nadeau, Adam W Akerman, Robert E Stroud, Rupak Mukherjee, Jeffrey A Jones
OBJECTIVE: Membrane type-1 matrix metalloproteinase (MT1-MMP) is elevated during thoracic aortic aneurysm (TAA) development in mouse models, and plays an important role in the activation of matrix metalloproteinase (MMP)-2 and the release of matrix- bound transforming growth factor-β. In this study, we tested the hypothesis that MT1-MMP is subject to protein kinase C (PKC)-mediated regulation, which alters intracellular trafficking and activity with TAAs. METHODS: Levels of MMP-2, native and phosphorylated MT1-MMP, and PKC-δ were measured in aortic tissue from patients with small TAAs (<5 cm; n = 8) and large TAAs (>6...
November 14, 2016: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/27922607/endocytosis-following-dopamine-d2-receptor-activation-is-critical-for-neuronal-activity-and-dendritic-spine-formation-via-rabex-5-pdgfr%C3%AE-signaling-in-striatopallidal-medium-spiny-neurons
#12
N Shioda, Y Yabuki, Y Wang, M Uchigashima, T Hikida, T Sasaoka, H Mori, M Watanabe, M Sasahara, K Fukunaga
Aberrant dopamine D2 receptor (D2R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. Here, we report that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early-endosome formation...
December 6, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27921095/journey-from-the-center-of-the-cell-the-intra-and-intercellular-transport-of-mrna
#13
Anna Kasprowicz-Maluśki, Wojciech Kwiatkowski, Alicja Starosta, Przemysław Wojtaszek
Transport and localized translation of mRNA is crucial for the proper spatiotemporal organization of proteins within cells. Distribution of RNAs to subcellular domains has recently emerged as a major mechanism for establishing functionally distinct compartments and structures in the cells. There is an emerging evidence that active transport of mRNA involves cytoskeleton and membrane trafficking pathways in fungi, plants and animals, suggesting that it is a common phenomenon among eukaryotes. The important highlights are that the RNA-binding proteins recognize the cargo mRNA and that RNPs are actively transported on the cytoskeletal tracks or co-transported with membranous compartments, such as the endoplasmic reticulum and endosomes...
December 6, 2016: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/27920523/pegylated-and-nanoparticle-conjugated-sulfonium-salt-photo-triggers-necrotic-cell-death
#14
Alaa A Fadhel, Xiling Yue, Ebrahim H Ghazvini Zadeh, Mykhailo V Bondar, Kevin D Belfield
Photodynamic therapy (PDT) processes involving the production of singlet oxygen face the issue of oxygen concentration dependency. Despite high oxygen delivery, a variety of properties related to metabolism and vascular morphology in cancer cells result in hypoxic environments, resulting in limited effectiveness of such therapies. An alternative oxygen-independent agent whose cell cytotoxicity can be remotely controlled by light may allow access to treatment of hypoxic tumors. Toward that end, we developed and tested both polyethylene glycol (PEG)-functionalized and hydrophilic silica nanoparticle (SiNP)-enriched photoacid generator (PAG) as a nontraditional PDT agent to effectively induce necrotic cell death in HCT-116 cells...
2016: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/27920219/the-proprotein-convertases-in-hypercholesterolemia-and-cardiovascular-diseases-emphasis-on-proprotein-convertase-subtilisin-kexin-9
#15
REVIEW
Nabil G Seidah, Marianne Abifadel, Stefan Prost, Catherine Boileau, Annik Prat
The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development and/or in adulthood. The essential SKI-1/S1P cleaves membrane-bound transcription factors at nonbasic residues...
January 2017: Pharmacological Reviews
https://www.readbyqxmd.com/read/27920026/the-transcellular-propagation-and-intracellular-trafficking-of-%C3%AE-synuclein
#16
George K Tofaris, Michel Goedert, Maria Grazia Spillantini
Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfolded α-synuclein conformers, which can template the aggregation of soluble monomers and lead to cellular dysfunction, at least partly by interfering with membrane fusion events at synaptic terminals...
December 5, 2016: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/27919066/designed-proteins-induce-the-formation-of-nanocage-containing-extracellular-vesicles
#17
Jörg Votteler, Cassandra Ogohara, Sue Yi, Yang Hsia, Una Nattermann, David M Belnap, Neil P King, Wesley I Sundquist
Complex biological processes are often performed by self-organizing nanostructures comprising multiple classes of macromolecules, such as ribosomes (proteins and RNA) or enveloped viruses (proteins, nucleic acids and lipids). Approaches have been developed for designing self-assembling structures consisting of either nucleic acids or proteins, but strategies for engineering hybrid biological materials are only beginning to emerge. Here we describe the design of self-assembling protein nanocages that direct their own release from human cells inside small vesicles in a manner that resembles some viruses...
November 30, 2016: Nature
https://www.readbyqxmd.com/read/27918526/mycobacterium-tuberculosis-esxh-inhibits-escrt-dependent-cd4-t-cell-activation
#18
Cynthia Portal-Celhay, JoAnn M Tufariello, Smita Srivastava, Aleena Zahra, Thais Klevorn, Patricia S Grace, Alka Mehra, Heidi S Park, Joel D Ernst, William R Jacobs, Jennifer A Philips
Mycobacterium tuberculosis (Mtb) establishes a persistent infection, despite inducing antigen-specific T-cell responses. Although T cells arrive at the site of infection, they do not provide sterilizing immunity. The molecular basis of how Mtb impairs T-cell function is not clear. Mtb has been reported to block major histocompatibility complex class II (MHC-II) antigen presentation; however, no bacterial effector or host-cell target mediating this effect has been identified. We recently found that Mtb EsxH, which is secreted by the Esx-3 type VII secretion system, directly inhibits the endosomal sorting complex required for transport (ESCRT) machinery...
December 5, 2016: Nature Microbiology
https://www.readbyqxmd.com/read/27918020/effects-of-ovalbumin-protein-nanoparticle-vaccine-size-and-coating-on-dendritic-cell-processing
#19
Timothy Z Chang, Samantha S Stadmiller, Erika Staskevicius, Julie A Champion
Nanoparticle vaccine delivery platforms are a promising technology for enhancing vaccine immunogenicity. Protein nanoparticles (PNPs), made entirely from antigen, have been shown to induce protective immune responses against influenza. However, the fundamental mechanisms by which PNPs enhance component protein immunogenicity are not understood. Here, we investigate the role of size and coating of model ovalbumin (OVA) PNPs on particle uptake and trafficking, as well as on inflammation and maturation factor expression in dendritic cells (DCs) in vitro...
December 5, 2016: Biomaterials Science
https://www.readbyqxmd.com/read/27917878/spatiotemporal-control-of-interferon-induced-jak-stat-signalling-and-gene-transcription-by-the-retromer-complex
#20
Daniela Chmiest, Nanaocha Sharma, Natacha Zanin, Christine Viaris de Lesegno, Massiullah Shafaq-Zadah, Vonick Sibut, Florent Dingli, Philippe Hupé, Stephan Wilmes, Jacob Piehler, Damarys Loew, Ludger Johannes, Gideon Schreiber, Christophe Lamaze
Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation...
December 5, 2016: Nature Communications
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