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Pesquisa : D08.811.277.656.300.760.431 [Categoria DeCS]
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[PMID]:29050400
[Au] Autor:Fitzgerald JC; Zimprich A; Carvajal Berrio DA; Schindler KM; Maurer B; Schulte C; Bus C; Hauser AK; Kübler M; Lewin R; Bobbili DR; Schwarz LM; Vartholomaiou E; Brockmann K; Wüst R; Madlung J; Nordheim A; Riess O; Martins LM; Glaab E; May P; Schenke-Layland K; Picard D; Sharma M; Gasser T; Krüger R
[Ad] Endereço:Department of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen and German Centre for Neurodegenerative Diseases, Tübingen, Germany.
[Ti] Título:Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease.
[So] Source:Brain;140(9):2444-2459, 2017 Sep 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies.
[Mh] Termos MeSH primário: Proteínas de Choque Térmico HSP90/genética
Metformina/uso terapêutico
Mitocôndrias/efeitos dos fármacos
Doença de Parkinson/tratamento farmacológico
Doença de Parkinson/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Apoptose/efeitos dos fármacos
Estudos de Casos e Controles
Células Cultivadas
Fibroblastos/metabolismo
Proteínas de Choque Térmico HSP90/biossíntese
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Potencial da Membrana Mitocondrial/fisiologia
Mitocôndrias/genética
Mitocôndrias/metabolismo
Proteínas Mitocondriais/metabolismo
Mutação
NAD/metabolismo
Biogênese de Organelas
Consumo de Oxigênio
Doença de Parkinson/genética
Proteínas Quinases/metabolismo
Espécies Reativas de Oxigênio/metabolismo
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HSP90 Heat-Shock Proteins); 0 (Mitochondrial Proteins); 0 (Reactive Oxygen Species); 0 (TRAP1 protein, human); 0U46U6E8UK (NAD); 8L70Q75FXE (Adenosine Triphosphate); 9100L32L2N (Metformin); EC 2.7.- (Protein Kinases); EC 2.7.11.1 (PTEN-induced putative kinase); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx202


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[PMID]:28566324
[Au] Autor:Quirós PM; Prado MA; Zamboni N; D'Amico D; Williams RW; Finley D; Gygi SP; Auwerx J
[Ad] Endereço:Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
[Ti] Título:Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals.
[So] Source:J Cell Biol;216(7):2027-2045, 2017 Jul 03.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans-expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.
[Mh] Termos MeSH primário: Fator 4 Ativador da Transcrição/metabolismo
Metabolismo Energético
Genômica/métodos
Mitocôndrias/metabolismo
Doenças Mitocondriais/metabolismo
Proteínas Mitocondriais/metabolismo
Proteômica/métodos
Estresse Fisiológico
[Mh] Termos MeSH secundário: Fator 4 Ativador da Transcrição/genética
Animais
Biologia Computacional
Modelos Animais de Doenças
Endopeptidase Clp/genética
Endopeptidase Clp/metabolismo
Epigênese Genética
Regulação da Expressão Gênica
Redes Reguladoras de Genes
Predisposição Genética para Doença
Células HeLa
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Potencial da Membrana Mitocondrial
Camundongos
Camundongos Knockout
Mitocôndrias/patologia
Doenças Mitocondriais/genética
Doenças Mitocondriais/patologia
Proteínas Mitocondriais/genética
Fenótipo
Complexo de Endopeptidases do Proteassoma/metabolismo
Mapas de Interação de Proteínas
Proteólise
Proteoma
Proteínas Ribossômicas/genética
Proteínas Ribossômicas/metabolismo
Serina Endopeptidases/genética
Serina Endopeptidases/metabolismo
Transdução de Sinais
Fatores de Tempo
Transcriptoma
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATF4 protein, human); 0 (Atf4 protein, mouse); 0 (Mitochondrial Proteins); 0 (Proteome); 0 (Ribosomal Proteins); 145891-90-3 (Activating Transcription Factor 4); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.21.92 (CLPP protein, mouse); EC 3.4.21.92 (Endopeptidase Clp); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.4.99.- (ATP dependent 26S protease)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170602
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201702058


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[PMID]:28349827
[Au] Autor:Ding Y; Wang B; Chen X; Zhou Y; Ge J
[Ad] Endereço:Department of Hepatobiliary & Laparoscopic Surgery, Wuhan University Renmin Hospital, Wuhan, China.
[Ti] Título:Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2-mediated inhibition of PI3K/Akt signaling pathway.
[So] Source:Tumour Biol;39(3):1010428317694317, 2017 Mar.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Staurosporine, which is an inhibitor of a broad spectrum of protein kinases, has shown cytotoxicity on several human cancer cells. However, the underlying mechanism is not well understood. In this study, we examined whether and how this compound has an inhibitory action on phosphatidylinositol 3-kinase (PI3K)/Akt pathway in vitro using HepG2 human hepatocellular carcinoma cell line. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, respectively. Glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation were performed to detect protein-protein interactions. Small interfering RNA (siRNA) was used to silence the expression of targeted protein. We found that staurosporine significantly decreased cell viability and increased cell apoptosis in a concentration- and time-dependent manner in HepG2 cancer cells, along with the decreased expressions of PDK1 protein and Akt phosphorylation. Staurosporine was also found to enhance Omi/HtrA2 release from mitochondria. Furthermore, Omi/HtrA2 directly bound to PDK1. Pharmacological and genetic inhibition of Omi/HtrA2 restored protein levels of PDK1 and protected HepG2 cancer cells from staurosporine-induced cell death. In addition, staurosporine was found to activate autophagy. However, inhibition of autophagy exacerbated cell death under concomitant treatment with staurosporine. Taken together, our results indicate that staurosporine induced cytotoxicity response by inhibiting PI3K/Akt signaling pathway through Omi/HtrA2-mediated PDK1 degradation, and the process provides a novel mechanism by which staurosporine produces its therapeutic effects.
[Mh] Termos MeSH primário: Carcinoma Hepatocelular/tratamento farmacológico
Neoplasias Hepáticas/tratamento farmacológico
Proteínas Mitocondriais/metabolismo
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Serina Endopeptidases/metabolismo
Estaurosporina/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Carcinoma Hepatocelular/enzimologia
Carcinoma Hepatocelular/metabolismo
Carcinoma Hepatocelular/patologia
Inibidores Enzimáticos/farmacologia
Células Hep G2
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Neoplasias Hepáticas/enzimologia
Neoplasias Hepáticas/metabolismo
Neoplasias Hepáticas/patologia
Fosfatidilinositol 3-Quinases/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Mitochondrial Proteins); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.2 (pyruvate dehydrogenase (acetyl-transferring) kinase); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); H88EPA0A3N (Staurosporine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317694317


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[PMID]:28186560
[Au] Autor:Riar AK; Burstein SR; Palomo GM; Arreguin A; Manfredi G; Germain D
[Ad] Endereço:Department of Medicine, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY 10029, USA.
[Ti] Título:Sex specific activation of the ERα axis of the mitochondrial UPR (UPRmt) in the G93A-SOD1 mouse model of familial ALS.
[So] Source:Hum Mol Genet;26(7):1318-1327, 2017 Apr 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The mitochondrial unfolded protein response (UPRmt) is a transcriptional program aimed at restoring proteostasis in mitochondria. Upregulation of mitochondrial matrix proteases and heat shock proteins was initially described. Soon thereafter, a distinct UPRmt induced by misfolded proteins in the mitochondrial intermembrane space (IMS) and mediated by the estrogen receptor alpha (ERα), was found to upregulate the proteasome and the IMS protease OMI. However, the IMS-UPRmt was never studied in a neurodegenerative disease in vivo. Thus, we investigated the IMS-UPRmt in the G93A-SOD1 mouse model of familial ALS, since mutant SOD1 is known to accumulate in the IMS of neural tissue and cause mitochondrial dysfunction. As the ERα is most active in females, we postulated that a differential involvement of the IMS-UPRmt could be linked to the longer lifespan of females in the G93A-SOD1 mouse. We found a significant sex difference in the IMS-UPRmt, because the spinal cords of female, but not male, G93A-SOD1 mice showed elevation of OMI and proteasome activity. Then, using a mouse in which G93A-SOD1 was selectively targeted to the IMS, we demonstrated that the IMS-UPRmt could be specifically initiated by mutant SOD1 localized in the IMS. Furthermore, we showed that, in the absence of ERα, G93A-SOD1 failed to activate OMI and the proteasome, confirming the ERα dependence of the response. Taken together, these results demonstrate the IMS-UPRmt activation in SOD1 familial ALS, and suggest that sex differences in the disease phenotype could be linked to differential activation of the ERα axis of the IMS-UPRmt.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Receptor alfa de Estrogênio/genética
Mitocôndrias/genética
Superóxido Dismutase/genética
[Mh] Termos MeSH secundário: Proteases Dependentes de ATP/genética
Proteases Dependentes de ATP/metabolismo
Esclerose Amiotrófica Lateral/metabolismo
Esclerose Amiotrófica Lateral/patologia
Animais
Modelos Animais de Doenças
Receptor alfa de Estrogênio/metabolismo
Feminino
Proteínas de Choque Térmico/genética
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Masculino
Camundongos
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Complexo de Endopeptidases do Proteassoma/genética
Complexo de Endopeptidases do Proteassoma/metabolismo
Serina Endopeptidases/genética
Serina Endopeptidases/metabolismo
Caracteres Sexuais
Resposta a Proteínas não Dobradas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Estrogen Receptor alpha); 0 (Heat-Shock Proteins); 0 (Mitochondrial Proteins); EC 1.15.1.1 (SOD1 G93A protein); EC 1.15.1.1 (Superoxide Dismutase); EC 3.4.21.- (ATP-Dependent Proteases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.- (mitochondrial intermembrane space protease); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.21.108 (Htra2 protein, mouse); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx049


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[PMID]:28137643
[Au] Autor:Sun Y; Chao JR; Xu W; Pourpak A; Boyd K; Moshiach S; Qi GY; Fu A; Shao HR; Pounds S; Morris SW
[Ad] Endereço:Department of Oncology, ShiJiaZhuangShi First Hospital, 36 FanXiLu, ShiJiaZhuangShi, Hebei 050011, PR China; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA. Electronic address: yisun456@yahoo.com.
[Ti] Título:MLF1 is a proapoptotic antagonist of HOP complex-mediated survival.
[So] Source:Biochim Biophys Acta;1864(4):719-727, 2017 04.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:In the HAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1 mice, with a doubling of the lifespan of Mlf1 /Hax1 animals compared to Hax1 animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.
[Mh] Termos MeSH primário: Linfopenia/genética
Metaloproteases/genética
Mitocôndrias/metabolismo
Proteínas Mitocondriais/genética
Proteínas/genética
Serina Endopeptidases/genética
[Mh] Termos MeSH secundário: Animais
Apoptose
Linfócitos B/metabolismo
Linfócitos B/patologia
Células COS
Sobrevivência Celular
Cercopithecus aethiops
Feminino
Fibroblastos/citologia
Fibroblastos/metabolismo
Deleção de Genes
Regulação da Expressão Gênica
Células HEK293
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Células K562
Linfopenia/mortalidade
Linfopenia/patologia
Linfopenia/prevenção & controle
Metaloproteases/metabolismo
Camundongos
Proteínas Mitocondriais/metabolismo
Proteínas/metabolismo
Serina Endopeptidases/metabolismo
Transdução de Sinais
Análise de Sobrevida
Linfócitos T/metabolismo
Linfócitos T/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Hs1bp1 protein, mouse); 0 (Mitochondrial Proteins); 0 (Mlf1 protein, mouse); 0 (Proteins); EC 3.4.- (Metalloproteases); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.105 (PARL protein, mouse); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.21.108 (Htra2 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170201
[St] Status:MEDLINE


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[PMID]:27848260
[Au] Autor:M'Angale PG; Staveley BE
[Ad] Endereço:Department of Biology, Memorial University of Newfoundland, St. John's, NL A1B 3X9, Canada.
[Ti] Título:The HtrA2 Drosophila model of Parkinson's disease is suppressed by the pro-survival Bcl-2 Buffy.
[So] Source:Genome;60(1):1-7, 2017 Jan.
[Is] ISSN:1480-3321
[Cp] País de publicação:Canada
[La] Idioma:eng
[Ab] Resumo:Mutations in High temperature requirement A2 (HtrA2), also designated PARK13, which lead to the loss of its protease activity, have been associated with Parkinson's disease (PD). HtrA2 is a mitochondrial protease that translocates to the cytosol upon the initiation of apoptosis where it participates in the abrogation of inhibitors of apoptosis (IAP) inhibition of caspases. Here, we demonstrate that the loss of the HtrA2 function in the dopaminergic neurons of Drosophila melanogaster results in PD-like phenotypes, and we attempt to restore the age-dependent loss in locomotor ability by co-expressing the sole pro-survival Bcl-2 homologue Buffy. The inhibition of HtrA2 in the dopaminergic neurons of Drosophila resulted in shortened lifespan and impaired climbing ability, and the overexpression of Buffy rescued the reduction in lifespan and the age-dependent loss of locomotor ability. In supportive experiments, the inhibition of HtrA2 in the Drosophila eye results in eye defects, marked by reduction in ommatidia number and increased disruption of the ommatidial array; phenotypes that are suppressed by the overexpression of Buffy.
[Mh] Termos MeSH primário: Proteínas de Drosophila/genética
Drosophila/genética
Drosophila/metabolismo
Doença de Parkinson/genética
Proteínas Proto-Oncogênicas c-bcl-2/genética
Serina Endopeptidases/genética
[Mh] Termos MeSH secundário: Envelhecimento/genética
Sequência de Aminoácidos
Animais
Sobrevivência Celular/genética
Sequência Conservada
Modelos Animais de Doenças
Proteínas de Drosophila/química
Proteínas de Drosophila/metabolismo
Expressão Gênica
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Locomoção/genética
Neurônios/metabolismo
Domínios PDZ
Doença de Parkinson/metabolismo
Doença de Parkinson/fisiopatologia
Fenótipo
Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
Serina Endopeptidases/química
Serina Endopeptidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (Proto-Oncogene Proteins c-bcl-2); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.21.108 (HtrA2 protein, Drosophila)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161117
[St] Status:MEDLINE
[do] DOI:10.1139/gen-2016-0069


  7 / 280 MEDLINE  
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[PMID]:26965693
[Au] Autor:Goo HG; Rhim H; Kang S
[Ad] Endereço:Division of Life Sciences, Korea University, Seoul 136-701, Korea.
[Ti] Título:Pathogenic Role of Serine Protease HtrA2/Omi in Neurodegenerative Diseases.
[So] Source:Curr Protein Pept Sci;18(7):746-757, 2017.
[Is] ISSN:1875-5550
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:High-temperature-requirement A2 (HtrA2)/Omi/PARK13 is a serine protease with extensive homology to the Escherichia coli HtrAs that are required for bacterial survival at high temperatures. The HtrA2 protein is a key modulator of mitochondrial molecular quality control but under stressful conditions it is released into the cytosol, where it promotes cell death by various pathways, including caspase-dependent pathway and ER stress-mediated apoptosis. Recently, the HtrA2 protein has received great attention for its potential role in neurodegeneration. Here, we review the current knowledge and pathophysiological functions of the HtrA2 protein in neurodegenerative disorders such as Parkinson's and Alzheimer's disease.
[Mh] Termos MeSH primário: Doença de Alzheimer/genética
Estresse do Retículo Endoplasmático/genética
Mitocôndrias/enzimologia
Proteínas Mitocondriais/genética
Doença de Parkinson/genética
Serina Endopeptidases/genética
[Mh] Termos MeSH secundário: Doença de Alzheimer/enzimologia
Doença de Alzheimer/patologia
Caspases/genética
Caspases/metabolismo
Domínio Catalítico
Morte Celular
Escherichia coli/genética
Escherichia coli/metabolismo
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Mitocôndrias/patologia
Proteínas Mitocondriais/metabolismo
Doença de Parkinson/enzimologia
Doença de Parkinson/patologia
Proteólise
Homologia de Sequência de Aminoácidos
Serina Endopeptidases/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Escherichia coli Proteins); 0 (Mitochondrial Proteins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.22.- (Caspases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160312
[St] Status:MEDLINE
[do] DOI:10.2174/1389203717666160311115750


  8 / 280 MEDLINE  
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[PMID]:27881096
[Au] Autor:Renaud M; Marcel C; Rudolf G; Schaeffer M; Lagha-Boukbiza O; Chanson JB; Chelly J; Anheim M; Tranchant C
[Ad] Endereço:Service of Neurology, University Hospital of Strasbourg, Hospital of Hautepierre, 1 avenue Molière, 67098, Strasbourg Cedex, France.
[Ti] Título:A step toward essential tremor gene discovery: identification of extreme phenotype and screening of HTRA2 and ANO3.
[So] Source:BMC Neurol;16(1):238, 2016 Nov 23.
[Is] ISSN:1471-2377
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Essential tremor (ET) is characterized by a frequent family history. No monogenic form of ET has been identified. We aimed at exploring ET patients to identify distinct subgroups and facilitate the identification of ET genes. We tested for the presence of HTRA2 p.G399S, and ANO3 p. W490C, p. R484 W and p. S685G mutations. METHODS: Between June 2011 and November 2013, all consecutive patients suspected with ET were prospectively included in a prospective, monocentric study. Family history, age at onset (AAO), features of tremor, benefit of alcohol and drugs, electrophysiological recording findings were collected. Sanger sequencing was performed for HTRA2 and ANO3 mutations screening. RESULTS: Sixty eight patients were investigated. Fourteen diagnosed with psychogenic (5) or dystonic tremor (9) were excluded. Regarding the 54 ET patients, mean AAO was 48 years (6-77), and mean disease duration 15 years (1-55). Bimodal distribution of AAO was consistent with phenotypic subgroups. In patients with AAO before 30 years, marked benefit of alcohol (p < 0.01) and ET family history (p < 0.01) were more frequent and the disease progression less severe (p < 0.0001). Neither HTRA2 nor ANO3 mutation were identified in our patients. CONCLUSIONS: Our data support that distinct ET phenotypic subgroups may be encountered. We recommend to study separately extreme phenotypes of ET, particularly autosomal dominant families with early AAO (<30 years) and marked benefit of alcohol, to facilitate the identification of ET genes. Electromyographic recording remains a support to distinguish ET from differential diagnosis. HTRA2 and ANO3 mutations are not common causes of ET.
[Mh] Termos MeSH primário: Distúrbios Distônicos/genética
Tremor Essencial/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idade de Início
Idoso
Idoso de 80 Anos ou mais
Anoctaminas
Canais de Cloreto/genética
Feminino
Estudos de Associação Genética
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Masculino
Meia-Idade
Proteínas Mitocondriais/genética
Mutação
Estudos Prospectivos
Serina Endopeptidases/genética
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANO3 protein, human); 0 (Anoctamins); 0 (Chloride Channels); 0 (Mitochondrial Proteins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161125
[St] Status:MEDLINE


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[PMID]:27571206
[Au] Autor:Gieldon A; Zurawa-Janicka D; Jarzab M; Wenta T; Golik P; Dubin G; Lipinska B; Ciarkowski J
[Ad] Endereço:Faculty of Chemistry, University of Gdansk, Wita Stwosza 63, 80-308, Gdansk, Poland.
[Ti] Título:Distinct 3D Architecture and Dynamics of the Human HtrA2(Omi) Protease and Its Mutated Variants.
[So] Source:PLoS One;11(8):e0161526, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:HtrA2(Omi) protease controls protein quality in mitochondria and plays a major role in apoptosis. Its HtrA2S306A mutant (with the catalytic serine routinely disabled for an X-ray study to avoid self-degradation) is a homotrimer whose subunits contain the serine protease domain (PD) and the regulatory PDZ domain. In the inactive state, a tight interdomain interface limits penetration of both PDZ-activating ligands and PD substrates into their respective target sites. We successfully crystalized HtrA2V226K/S306A, whose active counterpart HtrA2V226K has had higher proteolytic activity, suggesting higher propensity to opening the PD-PDZ interface than that of the wild type HtrA2. Yet, the crystal structure revealed the HtrA2V226K/S306A architecture typical of the inactive protein. To get a consistent interpretation of crystallographic data in the light of kinetic results, we employed molecular dynamics (MD). V325D inactivating mutant was used as a reference. Our simulations demonstrated that upon binding of a specific peptide ligand NH2-GWTMFWV-COOH, the PDZ domains open more dynamically in the wild type protease compared to the V226K mutant, whereas the movement is not observed in the V325D mutant. The movement relies on a PDZ vs. PD rotation which opens the PD-PDZ interface in a lid-like (budding flower-like in trimer) fashion. The noncovalent hinges A and B are provided by two clusters of interfacing residues, harboring V325D and V226K in the C- and N-terminal PD barrels, respectively. The opening of the subunit interfaces progresses in a sequential manner during the 50 ns MD simulation. In the systems without the ligand only minor PDZ shifts relative to PD are observed, but the interface does not open. Further activation-associated events, e.g. PDZ-L3 positional swap seen in any active HtrA protein (vs. HtrA2), were not observed. In summary, this study provides hints on the mechanism of activation of wtHtrA2, the dynamics of the inactive HtrA2V325D, but does not allow to explain an increased activity of HtrA2V226K.
[Mh] Termos MeSH primário: Proteínas Mitocondriais/química
Proteínas Mitocondriais/metabolismo
Serina Endopeptidases/química
Serina Endopeptidases/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Proteínas Mitocondriais/genética
Simulação de Dinâmica Molecular
Mutação/genética
Estrutura Secundária de Proteína
Estrutura Terciária de Proteína
Serina Endopeptidases/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mitochondrial Proteins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160830
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0161526


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[PMID]:27208207
[Au] Autor:Mandel H; Saita S; Edvardson S; Jalas C; Shaag A; Goldsher D; Vlodavsky E; Langer T; Elpeleg O
[Ad] Endereço:Metabolic Unit, Rambam Health Care Center, Rappaport School of Medicine, Technion, Haifa, Israel.
[Ti] Título:Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria.
[So] Source:J Med Genet;53(10):690-6, 2016 Oct.
[Is] ISSN:1468-6244
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cell survival critically depends on the integrity of mitochondria, which play a pivotal role during apoptosis. Extensive mitochondrial damage promotes release of pro-apoptotic factors from the intermembrane space of mitochondria. Released mitochondrial proteins include Smac/DIABLO and HTRA2/Omi, which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins. AIMS: Here we investigated the cause of extreme hypertonia at birth, alternating with hypotonia, with the subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, intractable seizures and early death in four patients from two unrelated families. The patients showed lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, evolving brain atrophy and disturbed cristae structure in muscle mitochondria. METHODS AND RESULTS: Using whole-exome sequencing, we identified missplicing mutation and a 5 bp deletion in HTRA2, encoding HTRA2/Omi. This protein was completely absent from the patients' fibroblasts, whose growth was impaired and which were hypersensitive to apoptosis. Expression of HtrA2/Omi or of the proteolytically inactive HTRA2/Omi protein restored the cells' apoptotic resistance. However, cell growth was only restored by the proteolytically active protein. CONCLUSIONS: This is the first report of recessive deleterious mutations in HTRA2 in human. The clinical phenotype, the increased apoptotic susceptibility and the impaired cell growth recapitulate those observed in the Htra2 knockout mice and in mutant mice with proteolytically inactive HTRA2/Omi. Together, they underscore the importance of both chaperone and proteolytic activities of HTRA2/Omi for balanced apoptosis sensitivity and for brain development. Absence of HTRA2/Omi is associated with severe neurodegenerative disorder of infancy, abnormal mitochondria, 3-methylglutaconic aciduria and increased sensitivity to apoptosis.
[Mh] Termos MeSH primário: Apoptose
Erros Inatos do Metabolismo/metabolismo
Mitocôndrias/metabolismo
Proteínas Mitocondriais/genética
Mutação
Doenças Neurodegenerativas/metabolismo
Serina Endopeptidases/genética
[Mh] Termos MeSH secundário: Animais
Análise Mutacional de DNA
Exoma
Evolução Fatal
Feminino
Serina Peptidase 2 de Requerimento de Alta Temperatura A
Seres Humanos
Lactente
Recém-Nascido
Masculino
Erros Inatos do Metabolismo/genética
Erros Inatos do Metabolismo/patologia
Erros Inatos do Metabolismo/fisiopatologia
Camundongos
Doenças Neurodegenerativas/genética
Doenças Neurodegenerativas/patologia
Doenças Neurodegenerativas/fisiopatologia
Linhagem
Síndrome
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mitochondrial Proteins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.108 (HTRA2 protein, human); EC 3.4.21.108 (High-Temperature Requirement A Serine Peptidase 2); EC 3.4.21.108 (Htra2 protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160522
[St] Status:MEDLINE
[do] DOI:10.1136/jmedgenet-2016-103922



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