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https://www.readbyqxmd.com/read/28448035/bioluminescence-imaging-of-neuroinflammation-in-transgenic-mice-after-peripheral-inoculation-of-alpha-synuclein-fibrils
#1
Sara Breid, Maria E Bernis, Julius B Tachu, Maria C Garza, Holger Wille, Gültekin Tamgüney
To study the prion-like behavior of misfolded alpha-synuclein, mouse models are needed that allow fast and simple transmission of alpha-synuclein prionoids, which cause neuropathology within the central nervous system (CNS). Here we describe that intraglossal or intraperitoneal injection of alpha-synuclein fibrils into bigenic Tg(M83(+/-):Gfap-luc(+/-)) mice, which overexpress human alpha-synuclein with the A53T mutation from the prion protein promoter and firefly luciferase from the promoter for glial fibrillary acidic protein (Gfap), is sufficient to induce neuropathologic disease...
April 13, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28447936/ppp1r15a-mediated-dephosphorylation-of-eif2%C3%AE-is-unaffected-by-sephin1-or-guanabenz
#2
Ana Crespillo-Casado, Joseph E Chambers, Peter M Fischer, Stefan J Marciniak, David Ron
Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylidene)amino]guanidines (Guanabenz and Sephin1) have been proposed to exert protective effects against misfolding by interfering with eIF2α-P dephosphorylation through selective disruption of a PP1-PPP1R15A holophosphatase complex. Surprisingly, they proved inert in vitro affecting neither stability of the PP1-PPP1R15A complex nor substrate-specific dephosphorylation...
April 27, 2017: ELife
https://www.readbyqxmd.com/read/28446709/control-of-mitochondrial-biogenesis-and-function-by-the-ubiquitin-proteasome-system
#3
REVIEW
Piotr Bragoszewski, Michal Turek, Agnieszka Chacinska
Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases...
April 2017: Open Biology
https://www.readbyqxmd.com/read/28444687/creutzfeldt-jakob-disease-lookback-study-21-years-of-surveillance-for-transfusion-transmission-risk
#4
Lauren A Crowder, Lawrence B Schonberger, Roger Y Dodd, Whitney R Steele
BACKGROUND: Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States...
April 25, 2017: Transfusion
https://www.readbyqxmd.com/read/28442264/mitochondrial-lon-protease-dependent-degradation-of-cytochrome-c-oxidase-subunits-under-hypoxia-and-myocardial-ischemia
#5
Naresh B V Sepuri, Rajesh Angireddy, Satish Srinivasan, Manti Guha, Joseph Spear, Bin Lu, Hindupur K Anandatheerthavarada, Carolyn K Suzuki, Narayan G Avadhani
The mitochondrial ATP dependent matrix protease, Lon, is involved in the maintenance of mitochondrial DNA nucleoids and degradation of abnormal or misfolded proteins. The Lon protease regulates mitochondrial Tfam (mitochondrial transcription factor A) level and thus modulates mitochondrial DNA (mtDNA) content. We have previously shown that hypoxic stress induces the PKA-dependent phosphorylation of cytochrome c oxidase (CcO) subunits I, IVi1, and Vb and a time-dependent reduction of these subunits in RAW 264...
April 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28441621/prion-like-transmission-of-pathogenic-protein-aggregates-in-genetic-models-of-neurodegenerative-disease
#6
REVIEW
Margaret Mp Pearce
A key pathological hallmark of most neurodegenerative diseases is the misfolding of a particular protein, leading to deposition of toxic protein aggregates in brain tissue. Recent data provide compelling evidence that pathogenic protein aggregates have prion-like properties-they self-replicate by templated misfolding of monomeric proteins and spread between individual cells. Studies in genetic model organisms have expanded our understanding of how prion-like pathogenic aggregates propagate in vivo, revealing potential roles for spreading along neural networks and key cellular processes in both neurons and glial cells...
April 22, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28441058/protein-misfolding-diseases
#7
F Ulrich Hartl
The majority of protein molecules must fold into defined three-dimensional structures to acquire functional activity. However, protein chains can adopt a multitude of conformational states, and their biologically active conformation is often only marginally stable. Metastable proteins tend to populate misfolded species that are prone to forming toxic aggregates, including soluble oligomers and fibrillar amyloid deposits, which are linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies...
April 24, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28439239/development-of-automated-patch-clamp-technique-to-investigate-cftr-chloride-channel-function
#8
Arnaud Billet, Lionel Froux, John W Hanrahan, Frederic Becq
The chloride (Cl(-)) channel cystic fibrosis transmembrane conductance regulator (CFTR) is defective in cystic fibrosis (CF), and mutation of its encoding gene leads to various defects such as retention of the misfolded protein in the endoplasmic reticulum, reduced stability at the plasma membrane, abnormal channel gating with low open probability, and thermal instability, which leads to inactivation of the channel at physiological temperature. Pharmacotherapy is one major therapeutic approach in the CF field and needs sensible and fast tools to identify promising compounds...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28438776/the-immunoproteasome-is-induced-by-cytokines-and-regulates-apoptosis-in-human-islets
#9
Morten Lundh, Marco Bugliani, Tina Dahlby, Danny Hung-Chieh Chou, Bridget Wagner, Seyed Mojtaba Ghiasi, Vincenzo De Tata, Zhifei Chen, Marianne Nissen Lund, Michael J Davies, Piero Marchetti, Thomas Mandrup-Poulsen
In addition to degrading misfolded and damaged proteins, the proteasome regulates the fate of cells in response to stress. The role of the proteasome in pro-inflammatory cytokine-induced human beta-cell apoptosis is unknown. INS-1, INS-1E and human islets were exposed to combinations of IFNγ, IL-1β and TNFα with or without addition of small molecules. Gene expression was assessed by microarray or quantitative PCR. Proteasome activities were analyzed using luminescent assays. Protein oxidation, Western blotting and electron microscopy were used to examine mechanisms underlying cytokine-induced apoptosis...
April 24, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28436203/endoplasmic-reticulum-proteostasis-impairment-in-aging
#10
REVIEW
Gabriela Martínez, Claudia Duran-Aniotz, Felipe Cabral-Miranda, Juan P Vivar, Claudio Hetz
Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function...
April 23, 2017: Aging Cell
https://www.readbyqxmd.com/read/28435985/elucidating-the-a%C3%AE-42-anti-aggregation-mechanism-of-action-of-tramiprosate-in-alzheimer-s-disease-integrating-molecular-analytical-methods-pharmacokinetic-and-clinical-data
#11
Petr Kocis, Martin Tolar, Jeremy Yu, William Sinko, Soumya Ray, Kaj Blennow, Howard Fillit, John A Hey
BACKGROUND: Amyloid beta (Aβ) oligomers play a critical role in the pathogenesis of Alzheimer's disease (AD) and represent a promising target for drug development. Tramiprosate is a small-molecule Aβ anti-aggregation agent that was evaluated in phase III clinical trials for AD but did not meet the primary efficacy endpoints; however, a pre-specified subgroup analysis revealed robust, sustained, and clinically meaningful cognitive and functional effects in patients with AD homozygous for the ε4 allele of apolipoprotein E4 (APOE4/4 homozygotes), who carry an increased risk for the disease...
April 24, 2017: CNS Drugs
https://www.readbyqxmd.com/read/28434076/%C3%AE-synuclein-nonhuman-primate-models-of-parkinson-s-disease
#12
REVIEW
David J Marmion, Jeffrey H Kordower
Proper understanding of the mechanism(s) by which α-synuclein misfolds and propagates may hold the key to unraveling the complex pathophysiology of Parkinson's disease. A more complete understanding of the disease itself, as well as establishing animal models that fully recapitulate pathological and functional disease progression, are needed to develop treatments that will delay, halt or reverse the disease course. Traditional neurotoxin-based animal models fail to mimic crucial aspects of Parkinson's and thus are not relevant for the study of neuroprotection and disease-modifying therapies...
April 22, 2017: Journal of Neural Transmission
https://www.readbyqxmd.com/read/28434003/cytotoxic-effects-of-transthyretin-aggregates-in-an-epidermoid-cell-line
#13
Vai Hong Fong, Amandio Vieira
OBJECTIVE: Skin amyloid deposits can occur as part of systemic amyloidoses including those involving misfolded- aggregated transthyretins (agTTR). Pathological effects of agTTR on the skin are not well understood. The main objective of the current study was to examine the toxicity of agTTR upon a human keratinocyte cell line. METHODS: Cells were analyzed for indicators of oxidative stress after treatment with normal soluble TTR or the same pre-aggregation concentration of agTTR...
April 22, 2017: Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28433717/response-a-chronic-effects-of-pbde-47-up-regulations-of-hsp60-and-hsp70-expression-in-freshwater-bivalve-anodonta-woodiana
#14
Xichao Xia, Shipeng Xue, Xiying Wang, Qingyuan Zhang, Chuanfeng Huang, Lianghong Guo, Lunguang Yao
Heat shock proteins (HSPs) play an important role in adaption of environmental stress by protein folding, membrane translocation, degradation of misfolded proteins and other regulatory processes. Our previous study showed oxidative stress generated from polybrominated diphenyl ether-47 (PBDE-47) could cause an acute toxicity on freshwater bivalve Anodonta Woodiana, but the effect of chronic toxicity need to be elucidated. In order to further investigate the chronic effect of PBDE-47, clams A. Woodiana were randomly divided into the PBDE-47 treated group administrated with PBDE-47 at a concentration 3...
April 19, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/28433684/activating-transcription-factor-6-dependent-sestrin-2-induction-ameliorates-er-stress-mediated-liver-injury
#15
Kyung Hwan Jegal, Sang Mi Park, Sam Seok Cho, Sung Hui Byun, Sae Kwang Ku, Sang Chan Kim, Sung Hwan Ki, Il Je Cho
Endoplasmic reticulum (ER) stress is characterized by an accumulation of misfolded proteins, and ER stress reduction is essential for maintaining tissue homeostasis. However, the molecular mechanisms that protect cells from ER stress are not completely understood. The present study investigated the role of sestrin 2 (SESN2) on ER stress and sought to elucidate the mechanism responsible for the hepatoprotective effect of SESN2 in vitro and in vivo. Treatment with tunicamycin (Tm) increased SESN2 protein and mRNA levels and reporter gene activity...
April 19, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28433661/differential-protein-acetylation-assists-import-of-excess-sod2-into-mitochondria-and-mediates-sod2-aggregation-associated-with-cardiac-hypertrophy-in-the-murine-sod2-tg-heart
#16
Liwen Zhang, Chwen-Lih Chen, Patrick T Kang, Zhicheng Jin, Yeong-Renn Chen
SOD2 is the primary antioxidant enzyme neutralizing ((•))O2((-)) in mitochondria. Cardiac-specific SOD2 overexpression (SOD2-tg) induces supernormal function and cardiac hypertrophy in the mouse heart. However, the reductive stress imposed by SOD2 overexpression results in protein aggregation of SOD2 pentamers and differential hyperacetylation of SOD2 in the mitochondria and cytosol. Here, we studied SOD2 acetylation in SOD2-tg and wild-type mouse hearts. LC-MS/MS analysis indicated the presence of four acetylated lysines in matrix SOD2 and nine acetylated lysines in cytosolic SOD2 from the SOD2-tg heart...
April 19, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28431247/the-ubiquitin-ligase-chip-integrates-proteostasis-and-aging-by-regulation-of-insulin-receptor-turnover
#17
Riga Tawo, Wojciech Pokrzywa, Éva Kevei, Melek E Akyuz, Vishnu Balaji, Svenja Adrian, Jörg Höhfeld, Thorsten Hoppe
Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that CHIP deficiency leads to increased levels of the insulin receptor (INSR) and reduced lifespan of worms and flies. The membrane-bound INSR regulates the insulin and IGF1 signaling (IIS) pathway and thereby defines metabolism and aging...
April 20, 2017: Cell
https://www.readbyqxmd.com/read/28431189/to-cure-or-not-to-cure-differential-effects-of-the-chaperone-sorting-factor-cur1-on-yeast-prions-are-mediated-by-the-chaperone-sis1
#18
Yury A Barbitoff, Andrew G Matveenko, Svetlana E Moskalenko, Olga M Zemlyanko, Gary P Newnam, Ayesha Patel, Tatiana A Chernova, Yury O Chernoff, Galina A Zhouravleva
Yeast self-perpetuating protein aggregates (prions) provide a convenient model for studying various components of the cellular protein quality control system. Molecular chaperones and chaperone-sorting factors, such as yeast Cur1 protein, play key role in proteostasis via tight control of partitioning and recycling of misfolded proteins. In this study, we show that, despite the previously described ability of Cur1 to antagonize the yeast prion [URE3], it enhances propagation and phenotypic manifestation of another prion, [PSI(+) ]...
April 21, 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28430800/the-burden-of-trisomy-21-disrupts-the-proteostasis-network-in-down-syndrome
#19
Stefanos Aivazidis, Christina M Coughlan, Abhishek K Rauniyar, Hua Jiang, L Alexander Liggett, Kenneth N Maclean, James R Roede
Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21. Abnormalities in chromosome number have the potential to lead to disruption of the proteostasis network (PN) and accumulation of misfolded proteins. DS individuals suffer from several comorbidities, and we hypothesized that disruption of proteostasis could contribute to the observed pathology and decreased cell viability in DS. Our results confirm the presence of a disrupted PN in DS, as several of its elements, including the unfolded protein response, chaperone system, and proteasomal degradation exhibited significant alterations compared to euploid controls in both cell and mouse models...
2017: PloS One
https://www.readbyqxmd.com/read/28429788/the-hsp90-chaperone-machinery
#20
REVIEW
Florian H Schopf, Maximilian M Biebl, Johannes Buchner
The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients...
April 21, 2017: Nature Reviews. Molecular Cell Biology
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