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https://www.readbyqxmd.com/read/28805003/protein-astrogliopathies-in-human-neurodegenerative-diseases-and-aging
#1
Gabor G Kovacs, Virginia M Lee, John Q Trojanowski
Neurodegenerative diseases are characterized by progressive dysfunction and loss of neurons associated with depositions of pathologically altered proteins showing hierarchical involvement of brain regions. The role of astrocytes in the pathogenesis of neurodegenerative diseases is explored as contributors to neuronal degeneration or neuroprotection pathways, and also as potential mediators of the transcellular spreading of disease-associated proteins. Protein astrogliopathy (PAG), including deposition of amyloid-β, prion protein, tau, α-synuclein, and very rarely transactive response DNA-binding protein 43 (TDP-43) is not unprecedented or unusual in neurodegenerative diseases...
September 2017: Brain Pathology
https://www.readbyqxmd.com/read/28803412/alpha-synuclein-oligomers-a-new-hope
#2
REVIEW
Nora Bengoa-Vergniory, Rosalind F Roberts, Richard Wade-Martins, Javier Alegre-Abarrategui
Alpha-synuclein is a protein implicated in Parkinson's disease and thought to be one of the main pathological drivers in the disease, although it remains unclear how this protein elicits its neurotoxic effects. Recent findings indicate that the assembly of toxic oligomeric species of alpha-synuclein may be one of the key processes for the pathology and spread of the disease. The absence of a sensitive in situ detection method has hindered the study of these oligomeric species and the role they play in the human brain until recently...
August 12, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28800967/role-of-prion-protein-in-premature-senescence-of-human-fibroblasts
#3
Emmanuelle Boilan, Virginie Winant, Elise Dumortier, Benaissa ElMoualij, Pascale Quatresooz, Heinz D Osiewacz, Florence Debacq-Chainiaux, Olivier Toussaint
Prion protein (PrP) is essentially known for its capacity to induce neurodegenerative prion diseases in mammals caused by a conformational change in its normal cellular isoform (PrP(C)) into an infectious and disease-associated misfolded form, called scrapie isoform (PrP(Sc)). Although its sequence is highly conserved, less information is available on its physiological role under normal conditions. However, increasing evidence supports a role for PrP(C) in the cellular response to oxidative stress. In the present study, a new link between PrP and senescence is highlighted...
August 8, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28800624/destabilizing-polymorphism-in-cervid-prion-protein-hydrophobic-core-determines-prion-conformation-and-conversion-efficiency
#4
Samia Hannaoui, Sara Amidian, Yo Ching Cheng, Camilo Duque Velásquez, Lyudmyla Dorosh, Sampson Law, Glenn Telling, Maria Stepanova, Debbie McKenzie, Holger Wille, Sabine Gilch
Prion diseases are infectious neurodegenerative disorders of humans and animals caused by misfolded forms of the cellular prion protein PrPC. Prions cause disease by converting PrPC into aggregation-prone PrPSc. Chronic wasting disease (CWD) is the most contagious prion disease with substantial lateral transmission, affecting free-ranging and farmed cervids. Although the PrP primary structure is highly conserved among cervids, the disease phenotype can be modulated by species-specific polymorphisms in the prion protein gene...
August 11, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28797122/cross-seeding-of-prions-by-aggregated-%C3%AE-synuclein-leads-to-transmissible-spongiform-encephalopathy
#5
Elizaveta Katorcha, Natallia Makarava, Young Jin Lee, Iris Lindberg, Mervyn J Monteiro, Gabor G Kovacs, Ilia V Baskakov
Aggregation of misfolded proteins or peptides is a common feature of neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's, prion and other diseases. Recent years have witnessed a growing number of reports of overlap in neuropathological features that were once thought to be unique to only one neurodegenerative disorder. However, the origin for the overlap remains unclear. One possibility is that diseases with mixed brain pathologies might arise from cross-seeding of one amyloidogenic protein by aggregated states of unrelated proteins...
August 10, 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28795797/molecular-dynamics-simulations-study-on-the-binding-and-stabilization-mechanism-of-antiprion-compounds-to-the-hot-spot-region-of-prpc
#6
Shuangyan Zhou, Xuewei Liu, Xiaoli An, Xiao-Jun Yao, Huanxiang Liu
Structural transitions in the prion protein from the cellular form, PrPC, into the pathological isoform, PrPSc, are regarded as the main cause of the transmissible spongiform encephalopathies, also known as prion diseases. Hence, discovering and designing effective antiprion drugs that can inhibit PrPC to PrPSc conversion is regarded as a promising way to cure prion disease. Among several strategies to inhibit PrPC to PrPSc conversion, to stabilize the native PrPC via specific binding is believed to be one of the valuable approach and many antiprion compounds have been reported based on this strategy...
August 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28794434/protective-role-of-cellular-prion-protein-against-tnf%C3%AE-mediated-inflammation-through-tace-%C3%AE-secretase
#7
Juliette Ezpeleta, François Boudet-Devaud, Mathéa Pietri, Anne Baudry, Vincent Baudouin, Aurélie Alleaume-Butaux, Nathalie Dagoneau, Odile Kellermann, Jean-Marie Launay, Benoit Schneider
Although cellular prion protein PrP(C) is well known for its implication in Transmissible Spongiform Encephalopathies, its functions remain elusive. Combining in vitro and in vivo approaches, we here show that PrP(C) displays the intrinsic capacity to protect neuronal cells from a pro-inflammatory TNFα noxious insult. Mechanistically, PrP(C) coupling to the NADPH oxidase-TACE α-secretase signaling pathway promotes TACE-mediated cleavage of transmembrane TNFα receptors (TNFRs) and the release of soluble TNFR, which limits the sensitivity of recipient cells to TNFα...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28791742/a-multispecific-monoclonal-antibody-g2-recognizes-at-least-three-completely-different-epitope-sequences-with-high-affinity
#8
Md Nuruddin Mahmud, Masayuki Oda, Daiki Usui, Yasuo Inoshima, Naotaka Ishiguro, Yuji O Kamatari
A monoclonal antibody (mAb) G2 possesses an unusual characteristic of reacting with at least three proteins (ATP6V1C1, SEPT3, and C6H10orf76) other than its original antigen, chicken prion protein (ChPrP). The epitopes on ChPrP and ATP6V1C1 have been identified previously. In this study, we identified the epitope in the third protein, SEPT3. Interestingly, there was no amino acid sequence similarity among the epitopes on the three proteins. These epitopes had high binding affinities to G2 (KD = ∼10(-7) M for monovalent binding and KD = ∼10(-9) M for divalent binding), as determined using a SPR biosensor...
August 9, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28791720/infectivity-in-bone-marrow-from-sporadic-cjd-patients
#9
Alvina Huor, Jean Yves Douet, Caroline Lacroux, Séverine Lugan, Cécile Tillier, Naima Aron, Hervé Cassard, Mark Arnold, Juan Maria Torres, James W Ironside, Olivier Andréoletti
Prion infectivity was recently identified in the blood of both sporadic and variant Creutzfeldt-Jakob disease (CJD) patients. In variant CJD (vCJD) the widespread distribution of prions in peripheral tissues of both asymptomatic and symptomatic patients is likely to explain the occurrence of the observed prionaemia. However, in sporadic CJD (sCJD) prion infectivity is described to be located principally in the central nervous system. In this study, we investigated the presence of prion infectivity in bone marrow collected after death in patients affected with different sCJD agents...
August 9, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28790319/novel-animal-model-defines-genetic-contributions-for-neuron-to-neuron-transfer-of-%C3%AE-synuclein
#10
Trevor Tyson, Megan Senchuk, Jason F Cooper, Sonia George, Jeremy M Van Raamsdonk, Patrik Brundin
Cell-to-cell spreading of misfolded α-synuclein (α-syn) is suggested to contribute to the progression of neuropathology in Parkinson's disease (PD). Compelling evidence supports the hypothesis that misfolded α-syn transmits from neuron-to-neuron and seeds aggregation of the protein in the recipient cells. Furthermore, α-syn frequently appears to propagate in the brains of PD patients following a stereotypic pattern consistent with progressive spreading along anatomical pathways. We have generated a C. elegans model that mirrors this progression and allows us to monitor α-syn neuron-to-neuron transmission in a live animal over its lifespan...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28790177/phosphorylation-of-the-fus-low-complexity-domain-disrupts-phase-separation-aggregation-and-toxicity
#11
Zachary Monahan, Veronica H Ryan, Abigail M Janke, Kathleen A Burke, Shannon N Rhoads, Gül H Zerze, Robert O'Meally, Gregory L Dignon, Alexander E Conicella, Wenwei Zheng, Robert B Best, Robert N Cole, Jeetain Mittal, Frank Shewmaker, Nicolas L Fawzi
Neuronal inclusions of aggregated RNA-binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation-prone, yeast prion-like, low sequence-complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in-cell phosphorylation sites across FUS LC We show that both phosphorylation and phosphomimetic variants reduce its aggregation-prone/prion-like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate...
August 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28783058/evolution-of-diagnostic-tests-for-chronic-wasting-disease-a-naturally-occurring-prion-disease-of-cervids
#12
REVIEW
Nicholas J Haley, Jürgen A Richt
Since chronic wasting disease (CWD) was first identified nearly 50 years ago in a captive mule deer herd in the Rocky Mountains of the United States, it has slowly spread across North America through the natural and anthropogenic movement of cervids and their carcasses. As the endemic areas have expanded, so has the need for rapid, sensitive, and cost effective diagnostic tests-especially those which take advantage of samples collected antemortem. Over the past two decades, strategies have evolved from the recognition of microscopic spongiform pathology and associated immunohistochemical staining of the misfolded prion protein to enzyme-linked immunoassays capable of detecting the abnormal prion conformer in postmortem samples...
August 5, 2017: Pathogens
https://www.readbyqxmd.com/read/28778104/to-what-extent-are-the-terminal-stages-of-sepsis-septic-shock-systemic-inflammatory-response-syndrome-and-multiple-organ-dysfunction-syndrome-actually-driven-by-a-prion-amyloid-form-of-fibrin
#13
Douglas B Kell, Etheresia Pretorius
No abstract text is available yet for this article.
August 4, 2017: Seminars in Thrombosis and Hemostasis
https://www.readbyqxmd.com/read/28772101/propagation-of-tau-aggregates-and-neurodegeneration
#14
Michel Goedert, David S Eisenberg, R Anthony Crowther
A pathway from the natively unfolded microtubule-associated protein Tau to a highly structured amyloid fibril underlies human Tauopathies. This ordered assembly causes disease and represents the gain of toxic function. In recent years, evidence has accumulated to suggest that Tau inclusions form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of pathology is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade...
July 25, 2017: Annual Review of Neuroscience
https://www.readbyqxmd.com/read/28771723/-prion-like-propagation-of-the-synucleinopathy-of-m83-transgenic-mice-depends-on-the-mouse-genotype-and-type-of-inoculum
#15
Dorian Sargent, Jérémy Verchere, Corinne Lazizzera, Damien Gaillard, Latifa Lakhdar, Nathalie Streichenberger, Eric Morignat, Dominique Bétemps, Thierry Baron
The M83 transgenic mouse is a model of human synucleinopathies that develops severe motor impairment correlated with accumulation of the pathological Ser129-phosphorylated α-synuclein (α-syn(P) ) in the brain and spinal cord. M83 disease can be accelerated by intracerebral inoculation of brain extracts from sick M83 mice. This has also recently been described using peripheral routes, injecting recombinant preformed α-syn fibrils into the muscle or the peritoneum. Here, we inoculated homozygous and/or hemizygous M83 neonates via the intraperitoneal and/or intracerebral routes with two different brain extracts: one from sick M83 mice inoculated with brain extract from other sick M83 mice, and the other derived from a human multiple system atrophy (MSA) source passaged in M83 mice...
August 3, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28768713/a-meta-analysis-and-review-examining-a-possible-role-for-oxidative-stress-and-singlet-oxygen-in-diverse-diseases
#16
REVIEW
Athinoula L Petrou, Athina Terzidaki
From kinetic data (k, T) we calculated the thermodynamic parameters for various processes (nucleation, elongation, fibrillization, etc.) of proteinaceous diseases that are related to the β-amyloid protein (Alzheimer's), to tau protein (Alzheimer's, Pick's), to α-synuclein (Parkinson's), prion, amylin (type II diabetes), and to α-crystallin (cataract). Our calculations led to ΔG(≠) values that vary in the range 92.8-127 kJ mol(-1) at 310 K. A value of ∼10-30 kJ mol(-1) is the activation energy for the diffusion of reactants, depending on the reaction and the medium...
August 2, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28766406/molecular-dynamics-simulations-of-hsp40%C3%A2-j-domain-mutants-identifies-disruption-of-the-critical-hpd-motif-as-the-key-factor-for-impaired-curing-in-vivo-of-the-yeast-prion-ure3
#17
You-Lin Xue, Hao Wang, Michael Riedy, Brittany-Lee Roberts, Yuna Sun, Yong-Bo Song, Gary W Jones, Daniel C Masison, Youtao Song
Genetic screens using Saccharomyces cerevisiae have identified an array of Hsp40 (Ydj1p) J-domain mutants that are impaired in the ability to cure the yeast [URE3] prion through disrupting functional interactions with Hsp70. However, biochemical analysis of some of these Hsp40 J-domain mutants has so far failed to provide major insight into the specific functional changes in Hsp40-Hsp70 interactions. To explore the detailed structural and dynamic properties of the Hsp40 J-domain, 20 ns molecular dynamic simulations of 4 mutants (D9A, D36A, A30T, and F45S) and wild-type J-domain were performed, followed by Hsp70 docking simulations...
August 2, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28765400/induction-of-iapp-amyloid-deposition-and-associated-diabetic-abnormalities-by-a-prion-like-mechanism
#18
Abhisek Mukherjee, Diego Morales-Scheihing, Natalia Salvadores, Ines Moreno-Gonzalez, Cesar Gonzalez, Kathleen Taylor-Presse, Nicolas Mendez, Mohammad Shahnawaz, A Osama Gaber, Omaima M Sabek, Daniel W Fraga, Claudio Soto
Although a large proportion of patients with type 2 diabetes (T2D) accumulate misfolded aggregates composed of the islet amyloid polypeptide (IAPP), its role in the disease is unknown. Here, we show that pancreatic IAPP aggregates can promote the misfolding and aggregation of endogenous IAPP in islet cultures obtained from transgenic mouse or healthy human pancreas. Islet homogenates immunodepleted with anti-IAPP-specific antibodies were not able to induce IAPP aggregation. Importantly, intraperitoneal inoculation of pancreatic homogenates containing IAPP aggregates into transgenic mice expressing human IAPP dramatically accelerates IAPP amyloid deposition, which was accompanied by clinical abnormalities typical of T2D, including hyperglycemia, impaired glucose tolerance, and a substantial reduction on β cell number and mass...
August 1, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28765208/plasma-cholesterol-level-determines-in-vivo-prion-propagation
#19
Veronique Perrier, Thibaut Imberdis, Pierre-Andre Lafon, Marina Cefis, Yunyun Wang, Elisabeth Huetter, Jacques-Damien Arnaud, Teresa Alvarez-Martinez, Naig Le Guern, Guillaume Maquart, Laurent Lagrost, Catherine Desrumaux
Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apolipoprotein B-containing lipoproteins, i.e. the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo...
August 1, 2017: Journal of Lipid Research
https://www.readbyqxmd.com/read/28765158/erratum-functional-prions-in-the-brain
#20
Joseph B Rayman, Eric R Kandel
No abstract text is available yet for this article.
August 1, 2017: Cold Spring Harbor Perspectives in Biology
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