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https://www.readbyqxmd.com/read/28432364/rrm-domain-of-als-ftd-causing-fus-characteristic-of-irreversible-unfolding-spontaneously-self-assembles-into-amyloid-fibrils
#1
Yimei Lu, Liangzhong Lim, Jianxing Song
526-residue FUS functions to self-assemble into reversible droplets/hydrogels, which could be further solidified into pathological fibrils. FUS is intrinsically prone to aggregation, composed of N-terminal low-sequence complexity (LC); RNA-recognition motif (RRM) and C-terminal LC domains. Intriguingly, previous in vivo studies revealed that its RRM is required for manifesting FUS cytotoxicity but the underlying mechanism remains unknown. Here, we characterized solution conformations of FUS and its five differentially dissected fragments, followed by detailed investigations on thermal unfolding, NMR dynamics and self-assembly of RRM...
April 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28431576/enhanced-neuroinvasion-by-smaller-soluble-prions
#2
Cyrus Bett, Jessica Lawrence, Timothy D Kurt, Christina Orru, Patricia Aguilar-Calvo, Anthony E Kincaid, Witold K Surewicz, Byron Caughey, Chengbiao Wu, Christina J Sigurdson
Infectious prion aggregates can propagate from extraneural sites into the brain with remarkable efficiency, likely transported via peripheral nerves. Yet not all prions spread into the brain, and the physical properties of a prion that is capable of transit within neurons remain unclear. We hypothesized that small, diffusible aggregates spread into the CNS via peripheral nerves. Here we used a structurally diverse panel of prion strains to analyze how the prion conformation impacts transit into the brain. Two prion strains form fibrils visible ultrastructurally in the brain in situ, whereas three strains form diffuse, subfibrillar prion deposits and no visible fibrils...
April 21, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28431525/membrane-enriched-proteome-changes-and-prion-protein-expression-during-neural-differentiation-and-in-neuroblastoma-cells
#3
J A Macedo, D Schrama, I Duarte, E Tavares, J Renaut, M E Futschik, P M Rodrigues, E P Melo
BACKGROUND: The function of the prion protein, involved in the so-called prion diseases, remains a subject of intense debate and the possibility that it works as a pleiotropic protein through the interaction with multiple membrane proteins is somehow supported by recent reports. Therefore, the use of proteomic and bioinformatics combined to uncover cellular processes occurring together with changes in the expression of the prion protein may provide further insight into the putative pleiotropic role of the prion protein...
April 22, 2017: BMC Genomics
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
#4
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/28430857/repurposed-drugs-targeting-eif2%C3%AE-p-mediated-translational-repression-prevent-neurodegeneration-in-mice
#5
Mark Halliday, Helois Radford, Karlijn A M Zents, Collin Molloy, Julie A Moreno, Nicholas C Verity, Ewan Smith, Catharine A Ortori, David A Barrett, Martin Bushell, Giovanna R Mallucci
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer's disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss...
April 19, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28430289/evidence-from-spatial-pattern-analysis-for-the-anatomical-spread-of-%C3%AE-synuclein-pathology-in-parkinson-s-disease-dementia
#6
Richard A Armstrong
<i>The objective of this study was to determine whether there is evidence from quantitative morphometry and spatial pattern analysis to support the hypothesis of anatomical spread of -synuclein in Parkinson's disease dementia (PDD). Hence, clustering of -synuclein-immunoreactive Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG) was studied in -synuclein-immunolabeled sections of cortical and limbic regions in 12 cases of PDD. The data suggested that: (1) LB, LN, and LG occurred in clusters which in 63% of regions were regularly distributed parallel to the tissue boundary, (2) in approximately 30% of cortical regions, the estimated cluster size of LB, LN, and LG was within the size range of cellular columns associated with the cortico-cortical pathways, (3) regularly distributed clusters were present in anatomically connected regions, and (4) the clustering pattern was similar to that of prion protein (PrPsc) deposits in Creutzfeldt-Jacob disease (CJD)...
2017: Folia Neuropathologica
https://www.readbyqxmd.com/read/28429419/semi-synthesis-of-murine-prion-protein-by-native-chemical-ligation-and-chemical-activation-for-preparation-of-polypeptide-%C3%AE-thioester
#7
Lei Shi, Huai Chen, Si-Yu Zhang, Ting-Ting Chu, Yu-Fen Zhao, Yong-Xiang Chen, Yan-Mei Li
Prions are suspected as pathogen of the fatal transmissible spongiform encephalopathies. Strategies to access homogenous prion protein (PrP) are required to fully comprehend the molecular mechanism of prion diseases. However, the polypeptide fragments from PrP show a high tendency to form aggregates, which is a gigantic obstacle of protein synthesis and purification. In this study, murine prion sequence 90 to 230 that is the core three-dimensional structure domain was constructed from three segments murine PrP (mPrP)(90-177), mPrP(178-212), and mPrP(213-230) by combining protein expression, chemical synthesis and chemical ligation...
April 21, 2017: Journal of Peptide Science: An Official Publication of the European Peptide Society
https://www.readbyqxmd.com/read/28429234/neuron-to-neuron-transfer-of-fus-in-drosophila-primary-neuronal-culture-is-enhanced-by-als-associated-mutations
#8
Sébastien Feuillette, Morgane Delarue, Gaëtan Riou, Anne-Lise Gaffuri, Jane Wu, Zsolt Lenkei, Olivier Boyer, Thierry Frébourg, Dominique Campion, Magalie Lecourtois
The DNA- and RNA-binding protein fused in sarcoma (FUS) has been pathologically and genetically linked to amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD). Cytoplasmic FUS-positive inclusions were identified in the brain and spinal cord of a subset of patients suffering with ALS/FTLD. An increasing number of reports suggest that FUS protein can behave in a prion-like manner. However, no neuropathological studies or experimental data were available regarding cell-to-cell spread of these pathological protein assemblies...
April 20, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28428956/physiological-functions-of-the-cellular-prion-protein
#9
REVIEW
Andrew R Castle, Andrew C Gill
The prion protein, PrP(C), is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrP(C) into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrP(C), allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrP(C) function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrP(C)...
2017: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/28428740/protein-quality-control-by-molecular-chaperones-in-neurodegeneration
#10
REVIEW
Aaron Ciechanover, Yong Tae Kwon
Protein homeostasis (proteostasis) requires the timely degradation of misfolded proteins and their aggregates by protein quality control (PQC), of which molecular chaperones are an essential component. Compared with other cell types, PQC in neurons is particularly challenging because they have a unique cellular structure with long extensions. Making it worse, neurons are postmitotic, i.e., cannot dilute toxic substances by division, and, thus, are highly sensitive to misfolded proteins, especially as they age...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28425641/molecular-dynamics-simulations-of-early-steps-in-rna-mediated-conversion-of-prions
#11
Erik J Alred, Michael Nguyen, Maggie Martin, Ulrich Hansmann
The rate-limiting step in prion diseases is the initial transition of a prion protein from its native form into a mis-folded state in which the protein not only forms cell-toxic aggregates but also becomes infectious. Recent experiments implicate polyadenosine RNA as a possible agent for generating the initial seed. In order to understand the mechanism of RNA-mediated mis-folding and aggregation of prions, we dock polyadenosine RNA to mouse and human prion models. Changes in stability and secondary structure of the prions upon binding to polyadenosine RNA are evaluated by comparing molecular dynamics simulations of these complexes with that of the unbound prions...
April 20, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28425516/mechanical-and-vibrational-characterization-of-amyloid-like-het-s-nanosheets-based-on-the-skewed-plate-theory
#12
Hyun Joon Chang, Myeongsang Lee, Jae In Kim, Gwonchan Yoon, Sungsoo Na
Pathological amyloidogenic prion proteins have a toxic effect on functional cells in the human cerebrum because of poor degradability and the tendency to accumulate in an uncontrolled manner under physiological conditions. HET-s, a fungal prion protein, is known to undergo conformational variations from fibrillar to nanosheet structures during a change from low to high pH conditions. It has been said that this conformational change can lead to self-propagation by nucleating on the lateral surface of singlet fibrils...
April 20, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28421568/prions-prionoid-complexes-and-amyloids-the-bad-the-good-and-something-in-between
#13
Iva Hafner Bratkovič
Prions are infectious agents causing transmissible spongiform encephalopathies in humans and animals. These protein-based particles template conformational changes in a host-encoded prion protein to an insoluble self-like conformation. Prions are also present in yeast, where they support protein-based epigenetic inheritance. There is emerging evidence that prion-like (prionoid) particles can support a variety of pathological and beneficial functions. The recent data on the prionoid spread of other pathological amyloids are discussed in light of differences between prions and prion-like aggregates...
April 19, 2017: Swiss Medical Weekly
https://www.readbyqxmd.com/read/28421536/lysosomal-quality-control-in-prion-diseases
#14
REVIEW
Priyanka Majumder, Oishee Chakrabarti
Prion diseases are transmissible, familial or sporadic. The prion protein (PrP), a normal cell surface glycoprotein, is ubiquitously expressed throughout the body. While loss of function of PrP does not elicit apparent phenotypes, generation of misfolded forms of the protein or its aberrant metabolic isoforms has been implicated in a number of neurodegenerative disorders such as scrapie, kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker and bovine spongiform encephalopathy...
April 18, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28421043/outlining-core-pathways-of-amyloid-toxicity-in-bacteria-with-the-repa-wh1-prionoid
#15
Laura Molina-García, María Moreno-Del Álamo, Pedro Botias, Zaira Martín-Moldes, María Fernández, Alicia Sánchez-Gorostiaga, Aída Alonso-Del Valle, Juan Nogales, Jesús García-Cantalejo, Rafael Giraldo
The synthetic bacterial prionoid RepA-WH1 causes a vertically transmissible amyloid proteinopathy in Escherichia coli that inhibits growth and eventually kills the cells. Recent in vitro studies show that RepA-WH1 builds pores through model lipid membranes, suggesting a possible mechanism for bacterial cell death. By comparing acutely (A31V) and mildly (ΔN37) cytotoxic mutant variants of the protein, we report here that RepA-WH1(A31V) expression decreases the intracellular osmotic pressure and compromise bacterial viability under either aerobic or anaerobic conditions...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28420656/posttranslational-modification-impact-on-the-mechanism-by-which-amyloid-%C3%AE-induces-synaptic-dysfunction
#16
Katarzyna M Grochowska, PingAn Yuanxiang, Julia Bär, Rajeev Raman, Gemma Brugal, Giriraj Sahu, Michaela Schweizer, Arthur Bikbaev, Stephan Schilling, Hans-Ulrich Demuth, Michael R Kreutz
Oligomeric amyloid-β (Aβ) 1-42 disrupts synaptic function at an early stage of Alzheimer's disease (AD). Multiple posttranslational modifications of Aβ have been identified, among which N-terminally truncated forms are the most abundant. It is not clear, however, whether modified species can induce synaptic dysfunction on their own and how altered biochemical properties can contribute to the synaptotoxic mechanisms. Here, we show that a prominent isoform, pyroglutamated Aβ3(pE)-42, induces synaptic dysfunction to a similar extent like Aβ1-42 but by clearly different mechanisms...
April 18, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28420443/tau-phosphorylation-induced-by-severe-closed-head-traumatic-brain-injury-is-linked-to-the-cellular-prion-protein
#17
Richard Rubenstein, Binggong Chang, Natalia Grinkina, Eleanor Drummond, Peter Davies, Meir Ruditzky, Deep Sharma, Kevin Wang, Thomas Wisniewski
Studies in vivo and in vitro have suggested that the mechanism underlying Alzheimer's disease (AD) neuropathogenesis is initiated by an interaction between the cellular prion protein (PrP(C)) and amyloid-β oligomers (Aβo). This PrP(C)-Aβo complex activates Fyn kinase which, in turn, hyperphosphorylates tau (P-Tau) resulting in synaptic dysfunction, neuronal loss and cognitive deficits. AD transgenic mice lacking PrP(C) accumulate Aβ, but show normal survival and no loss of spatial learning and memory suggesting that PrP(C) functions downstream of Aβo production but upstream of intracellular toxicity within neurons...
April 18, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28418021/prion-disease-a%C3%AE-pathology-in-human-growth-hormone-recipients
#18
Heather Wood
No abstract text is available yet for this article.
April 18, 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/28416787/a-family-with-hereditary-cerebellar-ataxia-finally-confirmed-as-gerstmann-straussler-scheinker-syndrome-with-p102l-mutation-in-prnp-gene
#19
Ling Long, Xiaodong Cai, Yaqing Shu, Zhengqi Lu
Gerstmann-Straussler-Scheinker syndrome (GSS) is an exceedingly rare prion disease. There are only 3 case reports of GSS in China. Here we report the first GSS family in southern China. A 47-year-old female complained of unsteady gait and dysarthria. Seven other individuals presented similar symptoms in 3 generations of her family, and all died 4-6 years after onset. To detect causative mutations, we employed a gene analysis panel of hereditary diseases. This revealed a P102L mutation in the prion protein gene (PRNP) gene, which is commonly found in GSS featuring cerebellar ataxia...
April 2017: Neurosciences: the Official Journal of the Pan Arab Union of Neurological Sciences
https://www.readbyqxmd.com/read/28415023/drosophila-models-of-prionopathies-insight-into-prion-protein-function-transmission-and-neurotoxicity
#20
REVIEW
Pedro Fernandez-Funez, Jonatan Sanchez-Garcia, Diego E Rincon-Limas
Prion diseases (PrD) are unique neurodegenerative conditions with sporadic, genetic, and infectious etiologies. The agent responsible for these pathologies is a misfolded conformation of the prion protein (PrP). Although a process of autocatalytic "conversion" is known to mediate disease transmission, important gaps still remain regarding the physiological function of PrP and its relevance to pathogenesis, the molecular and cellular mechanisms mediating neurotoxicity and transmission, and the PrP conformations responsible for neurotoxicity...
April 14, 2017: Current Opinion in Genetics & Development
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