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  1 / 4101 MEDLINE  
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[PMID]:28464931
[Au] Autor:Wulf MA; Senatore A; Aguzzi A
[Ad] Endereço:Institute of Neuropathology, University of Zurich, Rämistrasse 100, CH-8091, Zürich, Switzerland.
[Ti] Título:The biological function of the cellular prion protein: an update.
[So] Source:BMC Biol;15(1):34, 2017 05 02.
[Is] ISSN:1741-7007
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The misfolding of the cellular prion protein (PrP ) causes fatal neurodegenerative diseases. Yet PrP is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrP in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrP , but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrP in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.
[Mh] Termos MeSH primário: Sistema Nervoso Central/patologia
Sistema Nervoso Periférico/patologia
Doenças Priônicas/metabolismo
Proteínas Priônicas/metabolismo
[Mh] Termos MeSH secundário: Animais
Modelos Animais de Doenças
Camundongos
Doenças Priônicas/etiologia
Proteínas Priônicas/toxicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Prion Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1186/s12915-017-0375-5


  2 / 4101 MEDLINE  
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[PMID]:29304167
[Au] Autor:Caine D; Nihat A; Crabb P; Rudge P; Cipolotti L; Collinge J; Mead S
[Ad] Endereço:NHS National Prion Clinic, National Hospital for Neurology and Neurosurgery (NHNN), University College London Hospitals NHS Foundation Trust, London, United Kingdom.
[Ti] Título:The language disorder of prion disease is characteristic of a dynamic aphasia and is rarely an isolated clinical feature.
[So] Source:PLoS One;13(1):e0190818, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Akinetic mutism is a key diagnostic feature of prion diseases, however, their rapidly progressive nature makes detailed investigation of the language disorder in a large cohort extremely challenging. This study aims to position prion diseases in the nosology of language disorders and improve early clinical recognition. METHODS: A systematic, prospective investigation of language disorders in a large cohort of patients diagnosed with prion diseases. 568 patients were included as a sub-study of the National Prion Monitoring Cohort. All patients had at least one assessment with the MRC Scale, a milestone-based functional scale with language and non-language components. Forty patients, with early symptoms and able to travel to the study site, were also administered a comprehensive battery of language tests (spontaneous speech, semantics, syntax, repetition, naming, comprehension and lexical retrieval under different conditions). RESULTS: 5/568 (0.9%) patients presented with leading language symptoms. Those with repeated measurements deteriorated at a slower rate in language compared to non-language milestones. Amongst the subgroup of 40 patients who underwent detailed language testing, only three tasks-semantic and phonemic fluency and sentence comprehension-were particularly vulnerable early in the disease. These tasks were highly correlated with performance on non-verbal executive tests. Patients were also impaired on a test of dynamic aphasia. CONCLUSION: These results provide evidence that the language disorder in prion disease is rarely an isolated clinical or cognitive feature. The language abnormality is indicative of a dynamic aphasia in the context of a prominent dysexecutive syndrome, similar to that seen in patients with the degenerative movement disorder progressive supranuclear palsy (PSP).
[Mh] Termos MeSH primário: Afasia/complicações
Doenças Priônicas/complicações
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Feminino
Seres Humanos
Testes de Linguagem
Masculino
Meia-Idade
Testes Neuropsicológicos
Estudos Prospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180106
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190818


  3 / 4101 MEDLINE  
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[PMID]:28450269
[Au] Autor:Senesi M; Lewis V; Kim JH; Adlard PA; Finkelstein DI; Collins SJ
[Ad] Endereço:Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville 3010, Australia.
[Ti] Título:In vivo prion models and the disconnection between transmissibility and neurotoxicity.
[So] Source:Ageing Res Rev;36:156-164, 2017 Jul.
[Is] ISSN:1872-9649
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The primary causative event in the development of prion diseases is the misfolding of the normal prion protein (PrP ) into an ensemble of altered conformers (herein collectively denoted as PrP ) that accumulate in the brain. Prominent amongst currently unresolved key aspects underpinning prion disease pathogenesis is whether transmission and toxicity are sub-served by different molecular species of PrP , which may directly impact on the development of effective targeted treatments. The use of murine models of prion disease has been of fundamental importance for probing the relationship between hypothesised "neurotoxic" and "transmissible" PrP and the associated kinetic profiles of their production during disease evolution, but unfortunately consensus has not been achieved. Recent in vivo studies have led to formulation of the "two-phase" hypothesis, which postulates that there is first an exponential increase in transmitting PrP species followed by an abrupt transition to propagation of neurotoxic PrP species. Such observations however, appear inconsistent with previous in vivo murine studies employing detailed time-course behavioural testing, wherein evidence of neurotoxicity could be detected early in disease progression. This review analyses the contributions of in vivo murine models attempting to provide insights into the relationship between transmitting and neurotoxic PrP species and explores possible refinements to the "two-phase hypothesis", that better accommodate the available historical and recent evidence.
[Mh] Termos MeSH primário: Modelos Animais de Doenças
Doenças Priônicas/metabolismo
Doenças Priônicas/transmissão
Príons/metabolismo
Príons/toxicidade
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Encéfalo/patologia
Seres Humanos
Camundongos
Doenças Priônicas/patologia
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Prions)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  4 / 4101 MEDLINE  
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[PMID]:28749249
[Au] Autor:Hayashi Y; Iwasaki Y; Yoshikura N; Asano T; Mimuro M; Kimura A; Satoh K; Kitamoto T; Yoshida M; Inuzuka T
[Ad] Endereço:a Department of Neurology and Geriatrics , Gifu University Graduate School of Medicine , Gifu , Japan.
[Ti] Título:An autopsy-verified case of steroid-responsive encephalopathy with convulsion and a false-positive result from the real-time quaking-induced conversion assay.
[So] Source:Prion;11(4):284-292, 2017 Jul 04.
[Is] ISSN:1933-690X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We report an autopsy-verified case of steroid-responsive encephalopathy with convulsion and a false-positive result from the real-time quaking-induced conversion (RT-QUIC) assay. A 61-year-old Japanese man presented with acute onset of consciousness disturbance, and convulsions, but without a past medical or family history of progressive dementia, epilepsy, or prion disease. Brain diffusion and fluid-attenuated inverted recovery MR images revealed edematous cortical hyper-intensity, which diminished after the acute phase. Steroid pulse therapy was partially effective, although he continued to have dementia with myoclonus and psychiatric symptoms, despite resolution of the consciousness disturbance. Cerebrospinal fluid (CSF) analysis revealed a normal cell count, with significantly elevated levels of 14-3-3 protein and total tau protein. In addition, prion protein in the CSF was slowly amplified by the RT-QUIC assay. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. The patient died of sudden cardiac arrest at 3 months after the onset of symptoms. The positive result from the RT-QUIC assay led us to suspect involvement of prion disease, although a postmortem assessment revealed that he had pathological changes after convulsion, and no prion disease. This case indicates that convulsion may cause false-positive RT-QUIC results, and that a postmortem evaluation remains the gold standard for diagnosing similar cases.
[Mh] Termos MeSH primário: Encefalopatias/diagnóstico
Doenças Priônicas/diagnóstico
Príons/líquido cefalorraquidiano
Convulsões/diagnóstico
Esteroides/efeitos adversos
[Mh] Termos MeSH secundário: Proteínas 14-3-3/líquido cefalorraquidiano
Autopsia
Encefalopatias/líquido cefalorraquidiano
Encefalopatias/induzido quimicamente
Evolução Fatal
Seres Humanos
Masculino
Meia-Idade
Doenças Priônicas/líquido cefalorraquidiano
Convulsões/líquido cefalorraquidiano
Convulsões/induzido quimicamente
Proteínas tau/líquido cefalorraquidiano
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (Prions); 0 (Steroids); 0 (tau Proteins)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180111
[Lr] Data última revisão:
180111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1080/19336896.2017.1345416


  5 / 4101 MEDLINE  
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[PMID]:29176838
[Au] Autor:Goniotaki D; Lakkaraju AKK; Shrivastava AN; Bakirci P; Sorce S; Senatore A; Marpakwar R; Hornemann S; Gasparini F; Triller A; Aguzzi A
[Ad] Endereço:Institute of Neuropathology, University of Zurich, Zurich, Switzerland.
[Ti] Título:Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity.
[So] Source:PLoS Pathog;13(11):e1006733, 2017 Nov.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo. We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrPC antibodies in organotypic brain slices. Prion-mimetic antibodies increased mGluR5 clustering around dendritic spines, mimicking the toxicity of Aß oligomers. Oral treatment with the mGluR5 inhibitor, MPEP, delayed the onset of motor deficits and moderately prolonged survival of prion-infected mice. Although group-I mGluR inhibition was not curative, these results suggest that it may alleviate the neurological dysfunctions induced by prion diseases.
[Mh] Termos MeSH primário: Proteínas PrPC/toxicidade
Doenças Priônicas/tratamento farmacológico
Doenças Priônicas/metabolismo
Piridinas/administração & dosagem
Receptor de Glutamato Metabotrópico 5/metabolismo
Receptores de Glutamato Metabotrópico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Anticorpos/administração & dosagem
Feminino
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Neurônios/efeitos dos fármacos
Neurônios/metabolismo
Proteínas PrPC/genética
Proteínas PrPC/metabolismo
Doenças Priônicas/genética
Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores
Receptor de Glutamato Metabotrópico 5/genética
Receptores de Glutamato Metabotrópico/genética
Receptores de Glutamato Metabotrópico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (PrPC Proteins); 0 (Pyridines); 0 (Receptor, Metabotropic Glutamate 5); 0 (Receptors, Metabotropic Glutamate); 0 (metabotropic glutamate receptor type 1); 7VC0YVI27Y (6-methyl-2-(phenylethynyl)pyridine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006733


  6 / 4101 MEDLINE  
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[PMID]:29021298
[Au] Autor:Brundin P; Melki R
[Ad] Endereço:Van Andel Research Institute, Center for Neurodegenerative Science, Grand Rapids, Michigan 49503, and Patrik.Brundin@vai.org Ronald.Melki@cnrs.fr.
[Ti] Título:Prying into the Prion Hypothesis for Parkinson's Disease.
[So] Source:J Neurosci;37(41):9808-9818, 2017 Oct 11.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In Parkinson's disease, intracellular α-synuclein inclusions form in neurons. We suggest that prion-like behavior of α-synuclein is a key component in Parkinson's disease pathogenesis. Although multiple molecular changes are involved in the triggering of the disease process, we propose that neuron-to-neuron transfer is a crucial event that is essential for Lewy pathology to spread from one brain region to another. In this review, we describe key findings in human postmortem brains, cultured cells, and animal models of disease that support the idea that α-synuclein can act as a prion. We consider potential triggers of the α-synuclein misfolding and why the aggregates escape cellular degradation under disease conditions. We also discuss whether different strains of α-synuclein fibrils can underlie differences in cellular and regional distribution of aggregates in different synucleinopathies. Our conclusion is that α-synuclein probably acts as a prion in human diseases, and a deeper understanding of this step in the pathogenesis of Parkinson's disease can facilitate the development of disease-modifying therapies in the future. Parkinson's Disease Is Not Simply a Prion Disorder, by D. James Surmeier, José A. Obeso, and Glenda M. Halliday.
[Mh] Termos MeSH primário: Doença de Parkinson/patologia
Doenças Priônicas/patologia
[Mh] Termos MeSH secundário: Seres Humanos
Doença de Parkinson/etiologia
Doenças Priônicas/complicações
Príons
alfa-Sinucleína/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Prions); 0 (alpha-Synuclein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1788-16.2017


  7 / 4101 MEDLINE  
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[PMID]:29021297
[Au] Autor:Surmeier DJ; Obeso JA; Halliday GM
[Ad] Endereço:Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, j-surmeier@northwestern.edu.
[Ti] Título:Parkinson's Disease Is Not Simply a Prion Disorder.
[So] Source:J Neurosci;37(41):9799-9807, 2017 Oct 11.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The notion that prion-like spreading of misfolded α-synuclein (α-SYN) causes Parkinson's disease (PD) has received a great deal of attention. Although attractive in its simplicity, the hypothesis is difficult to reconcile with postmortem analysis of human brains and connectome-mapping studies. An alternative hypothesis is that PD pathology is governed by regional or cell-autonomous factors. Although these factors provide an explanation for the pattern of neuronal loss in PD, they do not readily explain the apparently staged distribution of Lewy pathology in many PD brains, the feature of the disease that initially motivated the spreading hypothesis by Braak and colleagues. While each hypothesis alone has its shortcomings, a synthesis of the two can explain much of what we know about the etiopathology of PD. Prying into the Prion Hypothesis for Parkinson's Disease, by Patrik Brundin and Ronald Melki.
[Mh] Termos MeSH primário: Doença de Parkinson/patologia
Doenças Priônicas/patologia
[Mh] Termos MeSH secundário: Seres Humanos
Corpos de Lewy/patologia
Doença de Parkinson/etiologia
Doenças Priônicas/complicações
Príons
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Prions)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171013
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1787-16.2017


  8 / 4101 MEDLINE  
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[PMID]:28880932
[Au] Autor:Igel-Egalon A; Moudjou M; Martin D; Busley A; Knäpple T; Herzog L; Reine F; Lepejova N; Richard CA; Béringue V; Rezaei H
[Ad] Endereço:INRA, Université Paris-Saclay, UR892, Virologie Immunologie Moléculaires, Jouy-en-Josas, France.
[Ti] Título:Reversible unfolding of infectious prion assemblies reveals the existence of an oligomeric elementary brick.
[So] Source:PLoS Pathog;13(9):e1006557, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mammalian prions, the pathogens that cause transmissible spongiform encephalopathies, propagate by self-perpetuating the structural information stored in the abnormally folded, aggregated conformer (PrPSc) of the host-encoded prion protein (PrPC). To date, no structural model related to prion assembly organization satisfactorily describes how strain-specified structural information is encoded and by which mechanism this information is transferred to PrPC. To achieve progress on this issue, we correlated the PrPSc quaternary structural transition from three distinct prion strains during unfolding and refolding with their templating activity. We reveal the existence of a mesoscopic organization in PrPSc through the packing of a highly stable oligomeric elementary subunit (suPrP), in which the strain structural determinant (SSD) is encoded. Once kinetically trapped, this elementary subunit reversibly loses all replicative information. We demonstrate that acquisition of the templating interface and infectivity requires structural rearrangement of suPrP, in concert with its condensation. The existence of such an elementary brick scales down the SSD support to a small oligomer and provide a basis of reflexion for prion templating process and propagation.
[Mh] Termos MeSH primário: Proteínas PrPC/metabolismo
Proteínas PrPSc/metabolismo
Doenças Priônicas/metabolismo
Desdobramento de Proteína
[Mh] Termos MeSH secundário: Animais
Doenças Transmissíveis
Camundongos
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PrPC Proteins); 0 (PrPSc Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006557


  9 / 4101 MEDLINE  
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[PMID]:28814578
[Au] Autor:Thackray AM; Cardova A; Wolf H; Pradl L; Vorberg I; Jackson WS; Bujdoso R
[Ad] Endereço:Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 OES, U.K.
[Ti] Título:Genetic human prion disease modelled in PrP transgenic .
[So] Source:Biochem J;474(19):3253-3267, 2017 Sep 20.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene and accumulation of PrP , an abnormal isomer of the normal host protein PrP , in the brain of affected individuals. PrP is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Adult transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic and show that inherited human prion disease can be modelled in this invertebrate host.
[Mh] Termos MeSH primário: Drosophila melanogaster/genética
Doenças Priônicas/genética
Proteínas Priônicas/genética
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Western Blotting
Cricetinae
Drosophila melanogaster/citologia
Drosophila melanogaster/efeitos dos fármacos
Endopeptidase K/metabolismo
Seres Humanos
Locomoção/efeitos dos fármacos
Camundongos
Microscopia Confocal
Mutação/genética
Neurotoxinas/toxicidade
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neurotoxins); 0 (Prion Proteins); EC 3.4.21.64 (Endopeptidase K)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170462


  10 / 4101 MEDLINE  
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[PMID]:28797122
[Au] Autor:Katorcha E; Makarava N; Lee YJ; Lindberg I; Monteiro MJ; Kovacs GG; Baskakov IV
[Ad] Endereço:Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
[Ti] Título:Cross-seeding of prions by aggregated α-synuclein leads to transmissible spongiform encephalopathy.
[So] Source:PLoS Pathog;13(8):e1006563, 2017 Aug.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. In the current study we examined whether prion replication can be induced by cross-seeding by α-synuclein or Aß peptide. We found that α-synuclein aggregates formed in cultured cells or in vitro display cross-seeding activity and trigger misfolding of the prion protein (PrPC) in serial Protein Misfolding Cyclic Amplification reactions, producing self-replicating PrP states characterized by a short C-terminal proteinase K (PK)-resistant region referred to as PrPres. Non-fibrillar α-synuclein or fibrillar Aß failed to cross-seed misfolding of PrPC. Remarkably, PrPres triggered by aggregated α-synuclein in vitro propagated in animals and, upon serial transmission, produced PrPSc and clinical prion disease characterized by spongiosis and astrocytic gliosis. The current study demonstrates that aggregated α-synuclein is potent in cross-seeding of prion protein misfolding and aggregation in vitro, producing self-replicating states that can lead to transmissible prion diseases upon serial passaging in wild type animals. In summary, the current work documents direct cross-seeding between unrelated amyloidogenic proteins associated with different neurodegenerative diseases. This study suggests that early interaction between unrelated amyloidogenic proteins might underlie the etiology of mixed neurodegenerative proteinopathies.
[Mh] Termos MeSH primário: Proteínas PrPSc/metabolismo
Doenças Priônicas/metabolismo
Doenças Priônicas/patologia
Príons/metabolismo
alfa-Sinucleína/metabolismo
[Mh] Termos MeSH secundário: Animais
Cricetinae
Seres Humanos
Mesocricetus
Camundongos
Dobramento de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (PrPSc Proteins); 0 (Prions); 0 (alpha-Synuclein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006563



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