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https://www.readbyqxmd.com/read/29145636/localization-and-functional-characterization-of-the-p-asn965ser-n965s-abca4-variant-in-mice-reveal-pathogenic-mechanisms-underlying-stargardt-macular-degeneration
#1
Laurie L Molday, Daniel Wahl, Marinko Sarunic, Robert S Molday
ABCA4 is a member of the superfamily of ATP-binding cassette (ABC) proteins that transports N-retinylidene-phosphatidylethanolamine (N-Ret-PE) across outer segment disc membranes thereby facilitating the removal of potentially toxic retinoid compounds from photoreceptor cells. Mutations in the gene encoding ABCA4 are responsible for Stargardt disease (STGD1), an autosomal recessive retinal degenerative disease that causes severe vision loss. To define the molecular basis for STGD1 associated with the p.Asn965Ser (N965S) mutation in the Walker A motif of nucleotide binding domain 1 (NBD1), we generated a p...
November 14, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/29145399/point-mutation-in-d8c-domain-of-tamm-horsfall-protein-uromodulin-in-transgenic-mice-causes-progressive-renal-damage-and-hyperuricemia
#2
Lijie Ma, Yan Liu, Nichole K Landry, Tarek M El-Achkar, John C Lieske, Xue-Ru Wu
Hereditary mutations in Tamm-Horsfall protein (THP/uromodulin) gene cause autosomal dominant kidney diseases characterized by juvenile-onset hyperuricemia, gout and progressive kidney failure, although the disease pathogenesis remains unclear. Here we show that targeted expression in transgenic mice of a mutation within the domain of 8 cysteines of THP in kidneys' thick ascending limb (TAL) caused unfolded protein response in younger (1-month old) mice and apoptosis in older (12-month old) mice. While the young mice had urine concentration defects and polyuria, such defects progressively reversed in the older mice to marked oliguria, highly concentrated urine, fibrotic kidneys and reduced creatinine clearance...
2017: PloS One
https://www.readbyqxmd.com/read/29145016/thermal-effect-on-the-degradation-of-hiapp20-29-fibrils
#3
H X Zhang, Lei Liu, Jie Wang, Christian Bortolini, Mingdong Dong
Uncontrolled misfolding of proteins resulting in the formation of amyloid deposits is associated with over 40 types of diseases, for instance, type-2 diabetes. The human Islet amyloid polypeptide (hIAPP) amyloid formation is thought to be the cause of type-2 diabetes occurrence. A possible strategy to the current challenge of reducing the toxicity of its aggregates to pancreatic β-cell is the discovery of an efficient way to degrading amyloid deposits. In this work, hIAPP20-29, a core fibrillating fragment of hIAPP, was selected as model system to explore the thermal effect at different temperature on the degradation of hIAPP20-29 mature fibrils...
October 31, 2017: Journal of Colloid and Interface Science
https://www.readbyqxmd.com/read/29143574/investigating-the-preventive-effects-of-baicalin-and-gallocatechin-aginst-glyoxal-induced-cystatin-aggregation
#4
Aamir Sohail, Waseem Feeroze Bhat, Mohammad Furkan, Aaliya Shah, Bilqees Bano
Several mammalian proteins form pathological deposits under nonphysiological conditions that are associated with many degenerative diseases. Protein aggregation is associated with aging, as well as a variety of diseases, including cystic fibrosis, amyotrophic lateral sclerosis (ALS), and hypertrophic cardiomyopathy. There is a lack of any potential anti-amyloidogenic agents and therapeutics till date. Polyphenols have been accredited with myriad biological effects. An analysis of the effects of natural agents like baicalin (BC) and gallocatechin (GC) on aggregation process can open new avenues for the treatment of protein misfolding diseases...
November 16, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/29143447/investigation-of-the-interactions-between-aptamer-and-misfolded-proteins-from-monomer-and-oligomer-to-fibril-by-single-molecule-force-spectroscopy
#5
Yan Zheng, Qing Wang, Xiaohai Yang, Zhiping Li, Lei Gao, Hua Zhang, Wenyan Nie, Xiuhua Geng, Kemin Wang
Increasing knowledge on the understanding interactions of aptamer with misfolded proteins (including monomer, oligomer, and amyloid fibril) is crucial for development of aggregation inhibitors and diagnosis of amyloid diseases. Herein, the interactions of lysozyme monomer-, oligomer-, and amyloid fibril-aptamer were investigated using single-molecule force spectroscopy. The results revealed that the aptamer screened against lysozyme monomer could also bind to oligomer and amyloid fibril, in spite of the recognition at a lower binding probability...
November 16, 2017: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/29142106/soluble-a%C3%AE-aggregates-can-inhibit-prion-propagation
#6
Claire J Sarell, Emma Quarterman, Daniel C-M Yip, Cassandra Terry, Andrew J Nicoll, Jonathan D F Wadsworth, Mark A Farrow, Dominic M Walsh, John Collinge
Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP(C)). Ligands that bind to PrP(C) can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP(C), and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation...
November 2017: Open Biology
https://www.readbyqxmd.com/read/29141431/development-of-isothermal-isobaric-replica-permutation-method-for-molecular-dynamics-and-monte-carlo-simulations-and-its-application-to-reveal-temperature-and-pressure-dependence-of-folded-misfolded-and-unfolded-states-of-chignolin
#7
Masataka Yamauchi, Hisashi Okumura
We developed a two-dimensional replica-permutation molecular dynamics method in the isothermal-isobaric ensemble. The replica-permutation method is a better alternative to the replica-exchange method. It was originally developed in the canonical ensemble. This method employs the Suwa-Todo algorithm, instead of the Metropolis algorithm, to perform permutations of temperatures and pressures among more than two replicas so that the rejection ratio can be minimized. We showed that the isothermal-isobaric replica-permutation method performs better sampling efficiency than the isothermal-isobaric replica-exchange method and infinite swapping method...
November 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/29140847/overexpressed-wild-type-superoxide-dismutase-1-exhibits-amyotrophic-lateral-sclerosis-related-misfolded-conformation-in-induced-pluripotent-stem-cell-derived-spinal-motor-neurons
#8
Kenichi Komatsu, Keiko Imamura, Hirofumi Yamashita, Jean-Pierre Julien, Ryosuke Takahashi, Haruhisa Inoue
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation...
November 14, 2017: Neuroreport
https://www.readbyqxmd.com/read/29139324/molecular-dynamics-simulations-and-novel-drug-discovery
#9
Xuewei Liu, Danfeng Shi, Shuangyan Zhou, Hongli Liu, Huanxiang Liu, Xiaojun Yao
Molecular dynamics (MD) simulations can provide not only plentiful dynamical structural information on biomacromolecules but also a wealth of energetic information about protein and ligand interactions. Such information is very important to understanding the structure-function relationship of the target and the essence of protein-ligand interactions and to guiding the drug discovery and design process. Thus, MD simulations have been applied widely and successfully in each step of modern drug discovery. Areas covered: In this review, the authors review the applications of MD simulations in novel drug discovery, including the pathogenic mechanisms of amyloidosis diseases, virtual screening and the interaction mechanisms between drugs and targets...
November 15, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29138676/resveratrol-modulation-of-protein-expression-in-parkin-mutant-human-skin-fibroblasts-a-proteomic-approach
#10
Daniele Vergara, Antonio Gaballo, Anna Signorile, Anna Ferretta, Paola Tanzarella, Consiglia Pacelli, Marco Di Paola, Tiziana Cocco, Michele Maffia
In this study, we investigated by two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) analysis the effects of resveratrol treatment on skin primary fibroblasts from a healthy subject and from a parkin-mutant early onset Parkinson's disease patient. Parkin, an E3 ubiquitin ligase, is the most frequently mutated gene in hereditary Parkinson's disease. Functional alteration of parkin leads to impairment of the ubiquitin-proteasome system, resulting in the accumulation of misfolded or aggregated proteins accountable for the neurodegenerative process...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29137994/role-of-osmolytes-in-protein-folding-and-aggregation-in-cells-and-its-applications-in-biotechnology
#11
REVIEW
Gulam Rabbani
Nature has selected osmolytes to protect intracellular macromolecules against denaturing stress conditions. These molecules are accumulated in the intracellular environment at considerably high concentrations. In general, osmolytes are known to stabilize proteins. Osmolytes are small naturally occurring compound that are utilized as chemical chaperones by changing the environmental condition in diseased cellular stress state. Osmolytes are present in different organisms, including microorganisms, animals and plants...
November 11, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/29135937/relax-cool-down-and-scaffold-how-to-restore-surface-expression-of-folding-deficient-mutant-gpcrs-and-slc6-transporters
#12
REVIEW
H M Mazhar Asjad, Shahrooz Nasrollahi-Shirazi, Sonja Sucic, Michael Freissmuth, Christian Nanoff
Many diseases arise from mutations, which impair protein folding. The study of folding-deficient variants of G protein-coupled receptors and solute carrier 6 (SLC6) transporters has shed light on the folding trajectory, how it is monitored and how misfolding can be remedied. Reducing the temperature lowers the energy barrier between folding intermediates and thereby eliminates stalling along the folding trajectory. For obvious reasons, cooling down is not a therapeutic option. One approach to rescue misfolded variants is to use membrane-permeable orthosteric ligands...
November 14, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29134561/cannabinoid-receptor-type-1-agonist-acea-protects-neurons-from-death-and-attenuates-endoplasmic-reticulum-stress-related-apoptotic-pathway-signaling
#13
Talita A Vrechi, Fernanda Crunfli, Andressa P Costa, Andréa S Torrão
Neurodegeneration is the result of progressive destruction of neurons in the central nervous system, with unknown causes and pathological mechanisms not yet fully elucidated. Several factors contribute to neurodegenerative processes, including neuroinflammation, accumulation of neurotoxic factors, and misfolded proteins in the lumen of the endoplasmic reticulum (ER). Endocannabinoid signaling has been pointed out as an important modulatory system in several neurodegeneration-related processes, inhibiting the inflammatory response and increasing neuronal survival...
November 13, 2017: Neurotoxicity Research
https://www.readbyqxmd.com/read/29134486/proteasome-associated-deubiquitinases-and-cancer
#14
Arjan Mofers, Paola Pellegrini, Stig Linder, Pádraig D'Arcy
Maintenance of protein homeostasis is a crucial process for the normal functioning of the cell. The regulated degradation of proteins is primarily facilitated by the ubiquitin proteasome system (UPS), a system of selective tagging of proteins with ubiquitin followed by proteasome-mediated proteolysis. The UPS is highly dynamic consisting of both ubiquitination and deubiquitination steps that modulate protein stabilization and degradation. Deregulation of protein stability is a common feature in the development and progression of numerous cancer types...
November 14, 2017: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/29131852/unraveling-the-key-to-the-resistance-of-canids-to-prion-diseases
#15
Natalia Fernández-Borges, Beatriz Parra, Enric Vidal, Hasier Eraña, Manuel A Sánchez-Martín, Jorge de Castro, Saioa R Elezgarai, Martí Pumarola, Tomás Mayoral, Joaquín Castilla
One of the characteristics of prions is their ability to infect some species but not others and prion resistant species have been of special interest because of their potential in deciphering the determinants for susceptibility. Previously, we developed different in vitro and in vivo models to assess the susceptibility of species that were erroneously considered resistant to prion infection, such as members of the Leporidae and Equidae families. Here we undertake in vitro and in vivo approaches to understand the unresolved low prion susceptibility of canids...
November 13, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29131016/focal-transplantation-of-aberrant-glial-cells-carrying-the-sod1g93a-mutation-into-rat-spinal-cord-induces-extensive-gliosis
#16
Sofía Ibarburu, Emiliano Trias, Natalia Lago, Hugo Peluffo, Romina Barreto-Núñez, Valentina Varela, Joseph S Beckman, Luis Barbeito
OBJECTIVE: We aimed to determine the potential of aberrant glial cells (AbAs) isolated from the spinal cord of adult SOD1G93A symptomatic rats to induce gliosis and neuronal damage following focal transplantation into the lumbar spinal cord of wild-type rats. METHODS: AbAs were obtained from the spinal cords of SOD1G93A symptomatic rats. One hundred thousand cells were injected using a glass micropipette into the lumbar spinal cords (L3-L5) of syngeneic wild-type adult rats...
November 1, 2017: Neuroimmunomodulation
https://www.readbyqxmd.com/read/29129774/crosstalk-between-endoplasmic-reticulum-stress-and-brain-inflammation-in-alzheimer-s-disease
#17
REVIEW
Luis E Santos, Sergio T Ferreira
While most often noted for its cognitive symptoms, Alzheimer's disease (AD) is, at its core, a disease of protein misfolding/aggregation, with an intriguing inflammatory component. Defective clearance and/or abnormal production of the amyloid-β peptide (Aβ), and its ensuing accumulation and aggregation, underlie two hallmark features of AD: brain accumulation of insoluble protein deposits known as amyloid or senile plaques, and buildup of soluble Aβ oligomers (AβOs), diffusible toxins linked to synapse dysfunction and memory impairment...
November 9, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/29129755/phylogenetic-analysis-predicts-structural-divergence-for-proteobacterial-clpc-proteins
#18
Justin M Miller, Hamza Chaudhary, Justin D Marsee
Regulated proteolysis is required in all organisms for the removal of misfolded or degradation-tagged protein substrates in cellular quality control pathways. The molecular machines that catalyze this process are known as ATP-dependent proteases with examples that include ClpAP and ClpCP. Clp/Hsp100 subunits form ring-structures that couple the energy of ATP binding and hydrolysis to protein unfolding and subsequent translocation of denatured protein into the compartmentalized ClpP protease for degradation...
November 9, 2017: Journal of Structural Biology
https://www.readbyqxmd.com/read/29129702/fkbp8-protects-the-heart-from-hemodynamic-stress-by-preventing-the-accumulation-of-misfolded-proteins-and-endoplasmic-reticulum-associated-apoptosis-in-mice
#19
Tomofumi Misaka, Tomokazu Murakawa, Kazuhiko Nishida, Yosuke Omori, Manabu Taneike, Shigemiki Omiya, Chris Molenaar, Yoshihiro Uno, Osamu Yamaguchi, Junji Takeda, Ajay M Shah, Kinya Otsu
Protein quality control in cardiomyocytes is crucial to maintain cellular homeostasis. The accumulation of damaged organelles, such as mitochondria and misfolded proteins in the heart is associated with heart failure. During the process to identify novel mitochondria-specific autophagy (mitophagy) receptors, we found FK506-binding protein 8 (FKBP8), also known as FKBP38, shares similar structural characteristics with a yeast mitophagy receptor, autophagy-related 32 protein. However, knockdown of FKBP8 had no effect on mitophagy in HEK293 cells or H9c2 myocytes...
November 9, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29127191/dysfunction-of-different-cellular-degradation-pathways-contributes-to-specific-%C3%AE-amyloid42-induced-pathologies
#20
Xuan-Ru Ji, Kuan-Chung Cheng, Yu-Ru Chen, Tzu-Yu Lin, Chun Hei Antonio Cheung, Chia-Lin Wu, Hsueh-Cheng Chiang
The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated β-amyloid (Aβ) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Aβ peptides and the pathogenesis underlying AD are unclear...
November 10, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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