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https://www.readbyqxmd.com/read/29777253/translation-inhibition-corrects-aberrant-localization-of-mutant-alanine-glyoxylate-aminotransferase-possible-therapeutic-approach-for-hyperoxaluria
#1
Ruth Belostotsky, Roman Lyakhovetsky, Michael Y Sherman, Fanny Shkedy, Shimrit Tzvi-Behr, Roi Bar, Bernd Hoppe, Björn Reusch, Bodo B Beck, Yaacov Frishberg
Primary hyperoxaluria type 1 is a severe kidney stone disease caused by abnormalities of the peroxisomal alanine-glyoxylate aminotransferase (AGT). The most frequent mutation G170R results in aberrant mitochondrial localization of the active enzyme. To evaluate the population of peroxisome-localized AGT, we developed a quantitative Glow-AGT assay based on the self-assembly split-GFP approach and used it to identify drugs that can correct mislocalization of the mutant protein. In line with previous reports, the Glow-AGT assay showed that mitochondrial transport inhibitors DECA and monensin increased peroxisomal localization of the mutant...
May 18, 2018: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://www.readbyqxmd.com/read/29776378/differential-induction-of-mutant-sod1-misfolding-and-aggregation-by-tau-and-%C3%AE-synuclein-pathology
#2
Michael C Pace, Guilian Xu, Susan Fromholt, John Howard, Benoit I Giasson, Jada Lewis, David R Borchelt
BACKGROUND: Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS: Mice expressing high levels of mutant forms of tau and α-synuclein (αSyn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation...
May 18, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29775068/embedding-a-metal-binding-motif-for-copper-transporter-into-a-lipid-bilayer-by-cu-i-binding
#3
Mariko Okada, Shinji Kajimoto, Takakazu Nakabayashi
Peptide-lipid interactions are widely involved with biologically significant phenomena, including the pathogenic mechanisms of protein misfolding diseases, and transmembrane protein folding. In this paper, the interaction of the cysteine/tryptophan (Cys/Trp) motif, which is a metal binding motif of copper transporter (Ctr) proteins, with a lipid bilayer was studied using fluorescence and circular dichroism (CD) spectroscopy. The binding of Cu(I) to the Cys/Trp motif induced a large red-edge excitation shift (REES) in the Trp fluorescence, indicating that the Trp residue is located inside the lipid bilayer following complexation of Cu(I) with the Cys/Trp motif...
May 18, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29773803/a-novel-small-molecule-chaperone-of-rod-opsin-and-its-potential-therapy-for-retinal-degeneration
#4
Yuanyuan Chen, Yu Chen, Beata Jastrzebska, Marcin Golczak, Sahil Gulati, Hong Tang, William Seibel, Xiaoyu Li, Hui Jin, Yong Han, Songqi Gao, Jianye Zhang, Xujie Liu, Hossein Heidari-Torkabadi, Phoebe L Stewart, William E Harte, Gregory P Tochtrop, Krzysztof Palczewski
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead to autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently is untreatable. Using a cell-based high-throughput screen (HTS) to identify small molecules that can stabilize the P23H-opsin mutant, which causes most cases of adRP, we identified a novel pharmacological chaperone of rod photoreceptor opsin, YC-001. As a non-retinoid molecule, YC-001 demonstrates micromolar potency and efficacy greater than 9-cis-retinal with lower cytotoxicity...
May 17, 2018: Nature Communications
https://www.readbyqxmd.com/read/29773177/participation-of-selenoproteins-localized-in-the-er-in-the-processes-occurring-in-this-organelle-and-in-the-regulation-of-carcinogenesis-associated-processes
#5
REVIEW
Elena Gennadyevna Varlamova
The functions performed by the ER are diverse: synthesis of steroid hormones, synthesis of proteins for the plasma membrane, lysosomes, as well as proteins meant for exocytosis, protein folding, formation of disulfide bonds, N-linked glycosylation, etc. Selenoproteins localized in this organelle are definitely involved in the processes occurring in it, and the most common of them include participation in protein degradation, regulation of ER stress and redox metabolism. ER stress has been registered in many types of cancer cells...
July 2018: Journal of Trace Elements in Medicine and Biology
https://www.readbyqxmd.com/read/29770957/first-in-rat-study-of-human-alzheimer-s-disease-tau-propagation
#6
Tomas Smolek, Santosh Jadhav, Veronika Brezovakova, Veronika Cubinkova, Bernadeta Valachova, Petr Novak, Norbert Zilka
One of the key features of misfolded tau in human neurodegenerative disorders is its propagation from one brain area into many others. In the last decade, in vivo tau spreading has been replicated in several mouse transgenic models expressing mutated human tau as well as in normal non-transgenic mice. In this study, we demonstrate for the first time that insoluble tau isolated from human AD brain induces full-blown neurofibrillary pathology in a sporadic rat model of tauopathy expressing non-mutated truncated tau protein...
May 16, 2018: Molecular Neurobiology
https://www.readbyqxmd.com/read/29770800/current-and-future-circulating-biomarkers-for-cardiac-amyloidosis
#7
REVIEW
Marco Luciani, Luca Troncone, Federica Del Monte
Cardiac amyloidosis (CA) comprises a heterogeneous group of medical conditions affecting the myocardium. It presents with proteinaceous infiltration with variable degrees of severity, prevalence and evolution. Despite this heterogeneity, erroneous protein folding is the common pathophysiologic process, yielding the formation of a single misfolded protein (monomer) that progressively evolves and ultimately forms amyloid fibers. Additionally, by seeding out from the organs of origin, intermediates called oligomers metastasize and restart the process...
May 17, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29769092/mineralization-of-alpha-1-antitrypsin-inclusion-bodies-in-mmalton-alpha-1-antitrypsin-deficiency
#8
Francesco Callea, Isabella Giovannoni, Paola Francalanci, Renata Boldrini, Gavino Faa, Daniela Medicina, Valerio Nobili, Valeer J Desmet, Kamal Ishak, Kuniaki Seyama, Emanuele Bellacchio
BACKGROUND: Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype. METHODS: This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients...
May 16, 2018: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/29768203/unconventional-secretion-mediates-the-trans-cellular-spreading-of-tau
#9
Taxiarchis Katsinelos, Marcel Zeitler, Eleni Dimou, Andromachi Karakatsani, Hans-Michael Müller, Eliana Nachman, Julia P Steringer, Carmen Ruiz de Almodovar, Walter Nickel, Thomas R Jahn
The progressive deposition of misfolded hyperphosphorylated tau is a pathological hallmark of tauopathies, including Alzheimer's disease. However, the underlying molecular mechanisms governing the intercellular spreading of tau species remain elusive. Here, we show that full-length soluble tau is unconventionally secreted by direct translocation across the plasma membrane. Increased secretion is favored by tau hyperphosphorylation, which provokes microtubule detachment and increases the availability of free protein inside cells...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29766802/endoplasmic-reticulum-stress-related-molecular-mechanisms-in-nonalcoholic-fatty-liver-disease-nafld
#10
Lifeng Wang, Jun Ren
Non-alcoholic fatty liver disease (NAFLD) has emerged as a common public health problem and a common cause of chronic liver diseases. However, the underlying mechanisms leading to the development and progression of NAFLD remain elusive. Accumulating evidence has depicted an essential role for endoplasmic reticulum (ER) stress in the development of steatosis and later progression into nonalcoholic steatohepatitis and hepatocarcinoma. With the accumulation of unfolded and misfolded proteins in the ER lumen, ER stress is provoked to turn on the unfolded protein response (UPR)...
May 16, 2018: Current Drug Targets
https://www.readbyqxmd.com/read/29766788/microbial-genetic-screens-for-monitoring-protein-misfolding-associated-with-neurodegeneration-tools-for-identifying-disease-relevant-genes-and-for-screening-synthetic-and-natural-compound-libraries-for-the-discovery-of-potential-therapeutics
#11
Kalliopi Kostelidou, Ilias Matis, Georgios Skretas
Neurodegenerative diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of high-throughput assays for the identification of cellular factors and processes that are important mediators of ND-associated proteotoxicities...
May 15, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29766738/the-role-of-gene-editing-in-neurodegenerative-diseases
#12
Hueng-Chuen Fan, Ching-Shiang Chi, Yih-Jing Lee, Jeng-Dau Tsai, Shinn-Zong Lin, Horng-Jyh Harn
Neurodegenerative diseases (NDs), at least including Alzheimer's, Huntington's, and Parkinson's diseases, have become the most dreaded maladies because there are no precise diagnostic tools or definite treatments for these debilitating diseases. The increased prevalence and a substantial impact on the social-economic and medical care of NDs propel governments to develop policies to counteract the impact. Although the etiologies of NDs are still unknown, growing evidence suggests that genetic, cellular, and circuit alternations may cause the generation of abnormal misfolded proteins, which uncontrolledly accumulate to damage and eventually overwhelm the protein-disposal mechanisms of these neurons, leading to a common pathological feature of NDs...
January 1, 2018: Cell Transplantation
https://www.readbyqxmd.com/read/29765555/a-protein-folding-molecular-imaging-biosensor-monitors-the-effects-of-drugs-that-restore-mutant-p53-structure-and-its-downstream-function-in-glioblastoma-cells
#13
Ramasamy Paulmurugan, Rayhaneh Afjei, Thillai V Sekar, Husam A Babikir, Tarik F Massoud
Misfolding mutations in the DNA-binding domain of p53 alter its conformation, affecting the efficiency with which it binds to chromatin to regulate target gene expression and cell cycle checkpoint functions in many cancers, including glioblastoma. Small molecule drugs that recover misfolded p53 structure and function may improve chemotherapy by activating p53-mediated senescence. We constructed and optimized a split Renilla luciferase (RLUC) complementation molecular biosensor (NRLUC-p53-CRLUC) to determine small molecule-meditated folding changes in p53 protein...
April 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29765356/soluble-and-cell-cell-mediated-drivers-of-proteasome-inhibitor-resistance-in-multiple-myeloma
#14
REVIEW
Mariah L Farrell, Michaela R Reagan
It is becoming clear that myeloma cell-induced disruption of the highly organized bone marrow components (both cellular and extracellular) results in destruction of the marrow and support for multiple myeloma (MM) cell proliferation, survival, migration, and drug resistance. Since the first phase I clinical trial on bortezomib was published 15 years ago, proteasome inhibitors (PIs) have become increasingly common for treatment of MM and are currently an essential part of any anti-myeloma combination therapy...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/29763589/%C3%AE-1-antitrypsin-polymerizes-in-alveolar-macrophages-of-smokers-with-and-without-%C3%AE-1-antitrypsin-deficiency
#15
Erica Bazzan, Mariaenrica Tinè, Davide Biondini, Riccardo Benetti, Simonetta Baraldo, Graziella Turato, Stefano Fagiuoli, Aurelio Sonzogni, Chiara Rigobello, Federico Rea, Fiorella Calabrese, Maria Pia Foschino-Barbaro, Elena Miranda, David A Lomas, Marina Saetta, Manuel G Cosio
BACKGROUND: The deficiency of α1 -antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z-AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AM) produce AAT, however it is not known if Z-AAT can polymerize in AM, further decreasing lung AAT and promoting lung inflammation. AIMS: To investigate if AAT polymerizes in human AM and to study the possible relation between polymerization and degree of lung inflammation...
May 12, 2018: Chest
https://www.readbyqxmd.com/read/29761205/cellular-mechanisms-responsible-for-cell-to-cell-spreading-of-prions
#16
REVIEW
Didier Vilette, Josquin Courte, Jean Michel Peyrin, Laurent Coudert, Laurent Schaeffer, Olivier Andréoletti, Pascal Leblanc
Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrPSc ). These abnormal aggregated PrPSc species multiply in infected cells by recruiting and converting the host PrPC protein into new PrPSc . How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrPSc -containing organelles through tunneling nanotubes...
May 14, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29760185/stability-of-an-aggregation-prone-partially-folded-state-of-human-profilin-1-correlates-with-aggregation-propensity
#17
Edoardo Del Poggetto, Angelo Toto, Chiara Aloise, Francesco Di Piro, Ludovica Gori, Francesco Malatesta, Stefano Gianni, Fabrizio Chiti, Francesco Bemporad
A set of missense mutations in the gene encoding profilin-1 has been linked to the onset of familiar forms of amyotrophic lateral sclerosis (fALS, also known as Lou Gehrig's disease). The pathogenic potential of these mutations is linked to the formation of intracellular inclusions of the mutant proteins and correlates with the mutation-induced destabilization of its native, fully folded state. However, the mechanism by which these mutations promote misfolding and self-assembly is yet unclear. Here, using temperature-jump and stopped-flow kinetic measurements, we show that, during refolding, wild-type profilin-1 transiently populates a partially folded (PF) state endowed with hydrophobic clusters exposed to the solvent and with no detectable secondary structure...
May 14, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29760094/salicylic-acid-independent-role-of-npr1-is-required-for-protection-from-proteotoxic-stress-in-the-plant-endoplasmic-reticulum
#18
Ya-Shiuan Lai, Luciana Renna, John Yarema, Cristina Ruberti, Sheng Yang He, Federica Brandizzi
The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60...
May 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29758300/alzheimer-s-disease-and-the-autophagic-lysosomal-system
#19
REVIEW
Kyung Min Chung, Nancy Hernández, Andrew Sproul, Wai Haung Yu
Age-related neurodegenerative diseases are of critical concern to the general population and research/medical community due to their health impact and socioeconomic consequences. A feature of most, if not all, neurodegenerative disorders is the presence of proteinopathies, in which misfolded or conformationally altered proteins drive disease progression and are often used as a primary neuropathological marker of disease. In particular, Alzheimer's disease (AD) is characterized by abnormal accumulation of protein aggregates, primarily extracellular plaques composed of the Aβ peptide and intracellular tangles comprised of the tau protein, both of which may indicate a primary defect in protein clearance...
May 11, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29757200/a-rationally-designed-hsp70-variant-rescues-the-aggregation-associated-toxicity-of-human-iapp-in-cultured-pancreatic-islet-%C3%AE-cells
#20
Marie Nicole Bongiovanni, Francesco Antonio Aprile, Pietro Sormanni, Michele Vendruscolo
Molecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised...
May 12, 2018: International Journal of Molecular Sciences
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