Base de dados : MEDLINE
Pesquisa : D12.776.441 [Categoria DeCS]
Referências encontradas : 2182 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 219 ir para página                         

  1 / 2182 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29346421
[Au] Autor:Higgins R; Kabbaj MH; Hatcher A; Wang Y
[Ad] Endereço:Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, Florida, United States of America.
[Ti] Título:The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins.
[So] Source:PLoS One;13(1):e0191490, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The functionality of a protein depends on its correct folding, but newly synthesized proteins are susceptible to aberrant folding and aggregation. Heat shock proteins (HSPs) function as molecular chaperones that aid in protein folding and the degradation of misfolded proteins. Trinucleotide (CAG) repeat expansion in the Huntingtin gene (HTT) results in the expression of misfolded Huntingtin protein (Htt), which contributes to the development of Huntington's disease. We previously found that the degradation of mutated Htt with polyQ expansion (Htt103QP) depends on both ubiquitin proteasome system and autophagy. However, the role of heat shock proteins in the clearance of mutated Htt remains poorly understood. Here, we report that cytosolic Hsp70 (Ssa family), its nucleotide exchange factors (Sse1 and Fes1), and a Hsp40 co-chaperone (Ydj1) are required for inclusion body formation of Htt103QP proteins and their clearance via autophagy. Extended induction of Htt103QP-GFP leads to the formation of a single inclusion body in wild-type yeast cells, but mutant cells lacking these HSPs exhibit increased number of Htt103QP aggregates. Most notably, we detected more aggregated forms of Htt103QP in sse1Δ mutant cells using an agarose gel assay. Increased protein aggregates are also observed in these HSP mutants even in the absence Htt103QP overexpression. Importantly, these HSPs are required for autophagy-mediated Htt103QP clearance, but are less critical for proteasome-dependent degradation. These findings suggest a chaperone network that facilitates inclusion body formation of misfolded proteins and the subsequent autophagic clearance.
[Mh] Termos MeSH primário: Autofagia
Proteínas de Choque Térmico/metabolismo
Proteína Huntingtina/genética
Mutação
Proteínas de Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/metabolismo
Repetições de Trinucleotídeos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Heat-Shock Proteins); 0 (Huntingtin Protein); 0 (Saccharomyces cerevisiae Proteins)
[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:180119
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191490


  2 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29324753
[Au] Autor:Langfelder P; Gao F; Wang N; Howland D; Kwak S; Vogt TF; Aaronson JS; Rosinski J; Coppola G; Horvath S; Yang XW
[Ad] Endereço:Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States of America.
[Ti] Título:MicroRNA signatures of endogenous Huntingtin CAG repeat expansion in mice.
[So] Source:PLoS One;13(1):e0190550, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In Huntington's disease (HD) patients and in model organisms, messenger RNA transcriptome has been extensively studied; in contrast, comparatively little is known about expression and potential role of microRNAs. Using RNA-sequencing, we have quantified microRNA expression in four brain regions and liver, at three different ages, from an allelic series of HD model mice with increasing CAG length in the endogenous Huntingtin gene. Our analyses reveal CAG length-dependent microRNA expression changes in brain, with 159 microRNAs selectively altered in striatum, 102 in cerebellum, 51 in hippocampus, and 45 in cortex. In contrast, a progressive CAG length-dependent microRNA dysregulation was not observed in liver. We further identify microRNAs whose transcriptomic response to CAG length expansion differs significantly among the brain regions and validate our findings in data from a second, independent cohort of mice. Using existing mRNA expression data from the same animals, we assess the possible relationships between microRNA and mRNA expression and highlight candidate microRNAs that are negatively correlated with, and whose predicted targets are enriched in, CAG-length dependent mRNA modules. Several of our top microRNAs (Mir212/Mir132, Mir218, Mir128 and others) have been previously associated with aspects of neuronal development and survival. This study provides an extensive resource for CAG length-dependent changes in microRNA expression in disease-vulnerable and -resistant brain regions in HD mice, and provides new insights for further investigation of microRNAs in HD pathogenesis and therapeutics.
[Mh] Termos MeSH primário: Proteína Huntingtina/genética
Doença de Huntington/genética
MicroRNAs/genética
Repetições de Trinucleotídeos
[Mh] Termos MeSH secundário: Animais
Encéfalo/metabolismo
Seres Humanos
Camundongos
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; VALIDATION STUDIES
[Nm] Nome de substância:
0 (HTT protein, human); 0 (Huntingtin Protein); 0 (MicroRNAs)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190550


  3 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28467905
[Au] Autor:Ramdzan YM; Trubetskov MM; Ormsby AR; Newcombe EA; Sui X; Tobin MJ; Bongiovanni MN; Gras SL; Dewson G; Miller JML; Finkbeiner S; Moily NS; Niclis J; Parish CL; Purcell AW; Baker MJ; Wilce JA; Waris S; Stojanovski D; Böcking T; Ang CS; Ascher DB; Reid GE; Hatters DM
[Ad] Endereço:Department of Biochemistry and Molecular Biology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia.
[Ti] Título:Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis.
[So] Source:Cell Rep;19(5):919-927, 2017 May 02.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Competing models exist in the literature for the relationship between mutant Huntingtin exon 1 (Httex1) inclusion formation and toxicity. In one, inclusions are adaptive by sequestering the proteotoxicity of soluble Httex1. In the other, inclusions compromise cellular activity as a result of proteome co-aggregation. Using a biosensor of Httex1 conformation in mammalian cell models, we discovered a mechanism that reconciles these competing models. Newly formed inclusions were composed of disordered Httex1 and ribonucleoproteins. As inclusions matured, Httex1 reconfigured into amyloid, and other glutamine-rich and prion domain-containing proteins were recruited. Soluble Httex1 caused a hyperpolarized mitochondrial membrane potential, increased reactive oxygen species, and promoted apoptosis. Inclusion formation triggered a collapsed mitochondrial potential, cellular quiescence, and deactivated apoptosis. We propose a revised model where sequestration of soluble Httex1 inclusions can remove the trigger for apoptosis but also co-aggregate other proteins, which curtails cellular metabolism and leads to a slow death by necrosis.
[Mh] Termos MeSH primário: Amiloide/metabolismo
Apoptose
Proteína Huntingtina/genética
[Mh] Termos MeSH secundário: Éxons
Células HEK293
Células HeLa
Seres Humanos
Proteína Huntingtina/metabolismo
Corpos de Inclusão/metabolismo
Potencial da Membrana Mitocondrial
Mutação
Espécies Reativas de Oxigênio/metabolismo
Ribonucleoproteínas/genética
Ribonucleoproteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid); 0 (HTT protein, human); 0 (Huntingtin Protein); 0 (Reactive Oxygen Species); 0 (Ribonucleoproteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  4 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29272284
[Au] Autor:Hensman Moss DJ; Robertson N; Farmer R; Scahill RI; Haider S; Tessari MA; Flynn G; Fischer DF; Wild EJ; Macdonald D; Tabrizi SJ
[Ad] Endereço:Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.
[Ti] Título:Quantification of huntingtin protein species in Huntington's disease patient leukocytes using optimised electrochemiluminescence immunoassays.
[So] Source:PLoS One;12(12):e0189891, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative condition caused by an expanded CAG repeat in the gene encoding huntingtin (HTT). Optimizing peripheral quantification of huntingtin throughout the course of HD is valuable not only to illuminate the natural history and pathogenesis of disease, but also to detect peripheral effects of drugs in clinical trial. RATIONALE: We previously demonstrated that mutant HTT (mHTT) was significantly elevated in purified HD patient leukocytes compared with controls and that these levels track disease progression. Our present study investigates whether the same result can be achieved with a simpler and more scalable collection technique that is more suitable for clinical trials. METHODS: We collected whole blood at 133 patient visits in two sample sets and generated peripheral blood mononuclear cells (PBMCs). Levels of mHTT, as well as N-, and C-terminal and mid-region huntingtin were measured in the PBMCs using ELISA-based Meso Scale Discovery (MSD) electrochemiluminescence immunoassay platforms, and we evaluated the relationship between different HTT species, disease stage, and brain atrophy on magnetic resonance imaging. CONCLUSIONS: The assays were sensitive and accurate. We confirm our previous findings that mHTT increases with advancing disease stage in patient PBMCs, this time using a simple collection protocol and scalable assay.
[Mh] Termos MeSH primário: Ensaio de Imunoadsorção Enzimática/métodos
Proteína Huntingtina/sangue
Doença de Huntington/sangue
Leucócitos/metabolismo
[Mh] Termos MeSH secundário: Encéfalo/diagnóstico por imagem
Estudos Transversais
Eletroquímica
Seres Humanos
Proteína Huntingtina/genética
Doença de Huntington/diagnóstico por imagem
Luminescência
Mutação
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (HTT protein, human); 0 (Huntingtin Protein)
[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:171223
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189891


  5 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28462988
[Au] Autor:Nikan M; Osborn MF; Coles AH; Biscans A; Godinho BMDC; Haraszti RA; Sapp E; Echeverria D; DiFiglia M; Aronin N; Khvorova A
[Ti] Título:Synthesis and Evaluation of Parenchymal Retention and Efficacy of a Metabolically Stable O-Phosphocholine-N-docosahexaenoyl-l-serine siRNA Conjugate in Mouse Brain.
[So] Source:Bioconjug Chem;28(6):1758-1766, 2017 06 21.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ligand-conjugated siRNAs have the potential to achieve targeted delivery and efficient silencing in neurons following local administration in the central nervous system (CNS). We recently described the activity and safety profile of a docosahexaenoic acid (DHA)-conjugated, hydrophobic siRNA (DHA-hsiRNA) targeting Huntingtin (Htt) mRNA in mouse brain. Here, we report the synthesis of an amide-modified, phosphocholine-containing DHA-hsiRNA conjugate (PC-DHA-hsiRNA), which closely resembles the endogenously esterified biological structure of DHA. We hypothesized that this modification may enhance neuronal delivery in vivo. We demonstrate that PC-DHA-hsiRNA silences Htt in mouse primary cortical neurons and astrocytes. After intrastriatal delivery, Htt-targeting PC-DHA-hsiRNA induces ∼80% mRNA silencing and 71% protein silencing after 1 week. However, PC-DHA-hsiRNA did not substantially outperform DHA-hsiRNA under the conditions tested. Moreover, at the highest locally administered dose (4 nmol, 50 µg), we observe evidence of PC-DHA-hsiRNA-mediated reactive astrogliosis. Lipophilic ligand conjugation enables siRNA delivery to neural tissues, but rational design of functional, nontoxic siRNA conjugates for CNS delivery remains challenging.
[Mh] Termos MeSH primário: Encéfalo/metabolismo
Sistemas de Liberação de Medicamentos/métodos
Tecido Parenquimatoso/metabolismo
RNA Interferente Pequeno/síntese química
[Mh] Termos MeSH secundário: Animais
Encéfalo/patologia
Ácidos Docosa-Hexaenoicos/química
Estabilidade de Medicamentos
Inativação Gênica
Proteína Huntingtina/genética
Camundongos
Fosforilcolina/química
Interferência de RNA
RNA Mensageiro
RNA Interferente Pequeno/administração & dosagem
RNA Interferente Pequeno/uso terapêutico
Serina/química
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Huntingtin Protein); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 107-73-3 (Phosphorylcholine); 25167-62-8 (Docosahexaenoic Acids); 452VLY9402 (Serine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00226


  6 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:29016656
[Au] Autor:Schuldenzucker V; Schubert R; Muratori LM; Freisfeld F; Rieke L; Matheis T; Schramke S; Motlik J; Kemper N; Radespiel U; Reilmann R
[Ad] Endereço:George-Huntington-Institute, Technology-Park, Muenster, Germany.
[Ti] Título:Behavioral testing of minipigs transgenic for the Huntington gene-A three-year observational study.
[So] Source:PLoS One;12(10):e0185970, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Large animal models of Huntington's disease (HD) may increase the reliability of translating preclinical findings to humans. Long live expectancy offers opportunities particularly for disease modifying approaches, but also challenges. The transgenic (tg) HD minipig model assessed in this study exhibits a high genetic homology with humans, similar body weight, and comparable brain structures. To test long-term safety, tolerability, and efficacy of novel therapeutic approaches in this model reliable assessments applicable longitudinally for several years are warranted for all phenotypical domains relevant in HD. OBJECTIVE: To investigate whether the tests proposed assessing motor, cognitive and behavioral domains can be applied repetitively over a 3-year period in minipigs with acceptable variability or learning effects and whether tgHD minipigs reveal changes in these domains compared to wildtype (wt) minipigs suggesting the development of an HD phenotype. METHODS: A cohort of 14 tgHD and 18 wt minipigs was followed for three years. Tests applied every six months included a tongue coordination and hurdle test for the motor domain, a color discrimination test for cognition, and a dominance test for assessing behavior. Statistical analyses were performed using repeated ANOVA for longitudinal group comparisons and Wilcoxon-tests for intra-visit differences between tgHD and wt minipigs. RESULTS: All tests applied demonstrated feasibility, acceptable variance and good consistency during the three-year period. No significant differences between tgHD and wt minipigs were detected suggesting lack of a phenotype before the age of four years. CONCLUSIONS: The assessment battery presented offers measures in all domains relevant for HD and can be applied in long-term phenotyping studies with tgHD minipigs. The observation of this cohort should be continued to explore the timeline of phenotype development and provide information for future interventional studies.
[Mh] Termos MeSH primário: Comportamento Animal/fisiologia
Doença de Huntington/fisiopatologia
Porco Miniatura/fisiologia
Suínos/fisiologia
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Feminino
Seres Humanos
Proteína Huntingtina/genética
Proteína Huntingtina/fisiologia
Aprendizagem/fisiologia
Língua/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Huntingtin Protein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171011
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185970


  7 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28938121
[Au] Autor:Guedes-Dias P; Holzbaur ELF
[Ad] Endereço:Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6085, USA.
[Ti] Título:Huntingtin Fibrils Poke Membranes.
[So] Source:Cell;171(1):32-33, 2017 09 21.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A hallmark of Huntington's disease is the presence of intracellular aggregates of mutant huntingtin, the pathological significance of which has long been debated. Using cryo-electron tomography, Bauerlein et al. reveal the fibrillary structure of huntingtin aggregates in situ and show that huntingtin fibrils interact with the endoplasmic reticulum, distorting its morphology and dynamics.
[Mh] Termos MeSH primário: Proteína Huntingtina
Proteínas do Tecido Nervoso/química
[Mh] Termos MeSH secundário: Animais
Retículo Endoplasmático
Seres Humanos
Doença de Huntington
Proteínas Nucleares/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Huntingtin Protein); 0 (Nerve Tissue Proteins); 0 (Nuclear Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170923
[St] Status:MEDLINE


  8 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28920889
[Au] Autor:Wild EJ; Tabrizi SJ
[Ad] Endereço:Huntington's Disease Centre, University College London Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK. Electronic address: e.wild@ucl.ac.uk.
[Ti] Título:Therapies targeting DNA and RNA in Huntington's disease.
[So] Source:Lancet Neurol;16(10):837-847, 2017 Oct.
[Is] ISSN:1474-4465
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:No disease-slowing treatment exists for Huntington's disease, but its monogenic inheritance makes it an appealing candidate for the development of therapies targeting processes close to its genetic cause. Huntington's disease is caused by CAG repeat expansions in the HTT gene, which encodes the huntingtin protein; development of therapies to target HTT transcription and the translation of its mRNA is therefore an area of intense investigation. Huntingtin-lowering strategies include antisense oligonucleotides and RNA interference targeting mRNA, and zinc finger transcriptional repressors and CRISPR-Cas9 methods aiming to reduce transcription by targeting DNA. An intrathecally delivered antisense oligonucleotide that aims to lower huntingtin is now well into its first human clinical trial, with other antisense oligonucleotides expected to enter trials in the next 1-2 years and virally delivered RNA interference and zinc finger transcriptional repressors in advanced testing in animal models. Recent advances in the design and delivery of therapies to target HTT RNA and DNA are expected to improve their efficacy, safety, tolerability, and duration of effect in future studies.
[Mh] Termos MeSH primário: Terapia Biológica/métodos
DNA
Proteína Huntingtina
Doença de Huntington/terapia
RNA
[Mh] Termos MeSH secundário: Animais
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Huntingtin Protein); 63231-63-0 (RNA); 9007-49-2 (DNA)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE


  9 / 2182 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28893927
[Au] Autor:Hong Y; Zhao T; Li XJ; Li S
[Ad] Endereço:Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322.
[Ti] Título:Mutant Huntingtin Inhibits αB-Crystallin Expression and Impairs Exosome Secretion from Astrocytes.
[So] Source:J Neurosci;37(39):9550-9563, 2017 Sep 27.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the brain, astrocytes secrete diverse substances that regulate neuronal function and viability. Exosomes, which are vesicles produced through the formation of multivesicular bodies and their subsequent fusion with the plasma membrane, are also released from astrocytes via exocytotic secretion. Astrocytic exosomes carry heat shock proteins that can reduce the cellular toxicity of misfolded proteins and prevent neurodegeneration. Although mutant huntingtin (mHtt) affects multiple functions of astrocytes, it remains unknown whether mHtt impairs the production of exosomes from astrocytes. We found that mHtt is not present in astrocytic exosomes, but can decrease exosome secretion from astrocytes in HD140Q knock-in (KI) mice. N-terminal mHtt accumulates in the nuclei and forms aggregates, causing decreased secretion of exosomes from cultured astrocytes. Consistently, there is a significant decrease in secreted exosomes in both female and male HD KI mouse striatum in which abundant nuclear mHtt aggregates are present. Conversely, injection of astrocytic exosomes into the striatum of HD140Q KI mice reduces the density of mHtt aggregates. Further, mHtt in astrocytes decreased the expression of αB-crystallin, a small heat shock protein that is enriched in astrocytes and mediates exosome secretion, by reducing the association of Sp1 with the enhancer of the α gene. Importantly, overexpression of αB-crystallin rescues defective exosome release from HD astrocytes as well as mHtt aggregates in the striatum of HD140Q KI mice. Our results demonstrate that mHtt reduces the expression of αB-crystallin in astrocytes to decrease exosome secretion in the HD brains, contributing to non-cell-autonomous neurotoxicity in HD. Huntington's disease (HD) is characterized by selective neurodegeneration that preferentially occurs in the striatal medium spiny neurons. Recent studies in different HD mouse models demonstrated that dysfunction of astrocytes, a major type of glial cell, leads to neuronal vulnerability. Emerging evidence shows that exosomes secreted from astrocytes contain neuroprotective cargoes that could support the survival of neighboring neurons. We found that mHtt in astrocytes impairs exosome secretion by decreasing αB-crystallin, a protein that is expressed mainly in glial cells and mediates exosome secretion. Overexpression of αB-crystallin could alleviate the deficient exosome release and neuropathology in HD mice. Our results revealed a new pathological pathway that affects the critical support of glial cells to neurons in the HD brain.
[Mh] Termos MeSH primário: Astrócitos/secreção
Exossomos/secreção
Proteína Huntingtina/genética
Doença de Huntington/metabolismo
Cadeia B de alfa-Cristalina/metabolismo
[Mh] Termos MeSH secundário: Animais
Astrócitos/metabolismo
Células Cultivadas
Corpo Estriado/metabolismo
Exocitose
Feminino
Proteína Huntingtina/metabolismo
Masculino
Camundongos
Mutação
Cadeia B de alfa-Cristalina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Htt protein, mouse); 0 (Huntingtin Protein); 0 (alpha-Crystallin B Chain)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1418-17.2017


  10 / 2182 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28890085
[Au] Autor:Bäuerlein FJB; Saha I; Mishra A; Kalemanov M; Martínez-Sánchez A; Klein R; Dudanova I; Hipp MS; Hartl FU; Baumeister W; Fernández-Busnadiego R
[Ad] Endereço:Department of Molecular Structural Biology, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
[Ti] Título:In Situ Architecture and Cellular Interactions of PolyQ Inclusions.
[So] Source:Cell;171(1):179-187.e10, 2017 Sep 21.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Expression of many disease-related aggregation-prone proteins results in cytotoxicity and the formation of large intracellular inclusion bodies. To gain insight into the role of inclusions in pathology and the in situ structure of protein aggregates inside cells, we employ advanced cryo-electron tomography methods to analyze the structure of inclusions formed by polyglutamine (polyQ)-expanded huntingtin exon 1 within their intact cellular context. In primary mouse neurons and immortalized human cells, polyQ inclusions consist of amyloid-like fibrils that interact with cellular endomembranes, particularly of the endoplasmic reticulum (ER). Interactions with these fibrils lead to membrane deformation, the local impairment of ER organization, and profound alterations in ER membrane dynamics at the inclusion periphery. These results suggest that aberrant interactions between fibrils and endomembranes contribute to the deleterious cellular effects of protein aggregation. VIDEO ABSTRACT.
[Mh] Termos MeSH primário: Doença de Huntington/patologia
Corpos de Inclusão/patologia
Neurônios/patologia
Neurônios/ultraestrutura
Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Amiloide/química
Animais
Microscopia Crioeletrônica
Retículo Endoplasmático/metabolismo
Retículo Endoplasmático/patologia
Feminino
Células HeLa
Seres Humanos
Proteína Huntingtina/genética
Proteína Huntingtina/metabolismo
Corpos de Inclusão/química
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Microscopia Eletrônica de Transmissão
Mutação
Agregação Patológica de Proteínas
Tomografia/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amyloid); 0 (HTT protein, human); 0 (Huntingtin Protein); 0 (Peptides); 26700-71-0 (polyglutamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE



página 1 de 219 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde