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Pesquisa : D08.811.037.250 [Categoria DeCS]
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[PMID]:28687604
[Au] Autor:Watchon M; Yuan KC; Mackovski N; Svahn AJ; Cole NJ; Goldsbury C; Rinkwitz S; Becker TS; Nicholson GA; Laird AS
[Ad] Endereço:Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales 2109, Australia.
[Ti] Título:Calpain Inhibition Is Protective in Machado-Joseph Disease Zebrafish Due to Induction of Autophagy.
[So] Source:J Neurosci;37(32):7782-7794, 2017 Aug 09.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The neurodegenerative disease Machado-Joseph disease (MJD), also known as spinocerebellar ataxin-3, affects neurons of the brain and spinal cord, disrupting control of the movement of muscles. We have successfully established the first transgenic zebrafish ( ) model of MJD by expressing human ataxin-3 protein containing either 23 glutamines (23Q, wild-type) or 84Q (MJD-causing) within neurons. Phenotypic characterization of the zebrafish (male and female) revealed that the ataxin-3-84Q zebrafish have decreased survival compared with ataxin-3-23Q and develop ataxin-3 neuropathology, ataxin-3 cleavage fragments and motor impairment. Ataxin-3-84Q zebrafish swim shorter distances than ataxin-3-23Q zebrafish as early as 6 days old, even if expression of the human ataxin-3 protein is limited to motor neurons. This swimming phenotype provides a valuable readout for drug treatment studies. Treating the EGFP-ataxin-3-84Q zebrafish with the calpain inhibitor compound calpeptin decreased levels of ataxin-3 cleavage fragments, but also removed all human ataxin-3 protein (confirmed by ELISA) and prevented the early MJD zebrafish motor phenotype. We identified that this clearance of ataxin-3 protein by calpeptin treatment resulted from an increase in autophagic flux (indicated by decreased p62 levels and increased LC3II). Cotreatment with the autophagy inhibitor chloroquine blocked the decrease in human ataxin-3 levels and the improved movement produced by calpeptin treatment. This study demonstrates that this first transgenic zebrafish model of MJD is a valuable tool for testing potential treatments for MJD. Calpeptin treatment is protective in this model of MJD and removal of human ataxin-3 through macro-autophagy plays an important role in this beneficial effect. We have established the first transgenic zebrafish model of the neurodegenerative disease MJD, and identified relevant disease phenotypes, including impaired movement from an early age, which can be used in rapid drug testing studies. We have found that treating the MJD zebrafish with the calpain inhibitor compound calpeptin produces complete removal of human ataxin-3 protein, due to induction of the autophagy quality control pathway. This improves the movement of the MJD zebrafish. Artificially blocking the autophagy pathway prevents the removal of human ataxin-3 and improved movement produced by calpeptin treatment. These findings indicate that induction of autophagy, and removal of ataxin-3 protein, plays an important role in the protective effects of calpain inhibition for the treatment of MJD.
[Mh] Termos MeSH primário: Ataxina-3/metabolismo
Autofagia/fisiologia
Calpaína/metabolismo
Modelos Animais de Doenças
Glicoproteínas/farmacologia
Doença de Machado-Joseph/metabolismo
Proteínas Repressoras/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Ataxina-3/genética
Autofagia/efeitos dos fármacos
Calpaína/antagonistas & inibidores
Calpaína/genética
Feminino
Glicoproteínas/uso terapêutico
Seres Humanos
Doença de Machado-Joseph/genética
Doença de Machado-Joseph/prevenção & controle
Masculino
Proteínas Repressoras/genética
Peixe-Zebra
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glycoproteins); 0 (Repressor Proteins); 0 (calpain inhibitors); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3); EC 3.4.22.- (Calpain)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.1142-17.2017


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[PMID]:28604978
[Au] Autor:Geng Y
[Ad] Endereço:Tangshan Vocational and Technical College, Tangshan, Hebei 063004, China. gengyu315@163.com.
[Ti] Título:[A pedigree affected with spinocerebellar ataxia type III].
[So] Source:Zhonghua Yi Xue Yi Chuan Xue Za Zhi;34(3):463-464, 2017 Jun 10.
[Is] ISSN:1003-9406
[Cp] País de publicação:China
[La] Idioma:chi
[Mh] Termos MeSH primário: Ataxias Espinocerebelares/genética
[Mh] Termos MeSH secundário: Adulto
Ataxina-3/genética
Feminino
Seres Humanos
Masculino
Meia-Idade
Linhagem
Proteínas Repressoras/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Repressor Proteins); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.3760/cma.j.issn.1003-9406.2017.03.037


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[PMID]:28445460
[Au] Autor:Ashkenazi A; Bento CF; Ricketts T; Vicinanza M; Siddiqi F; Pavel M; Squitieri F; Hardenberg MC; Imarisio S; Menzies FM; Rubinsztein DC
[Ad] Endereço:Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
[Ti] Título:Polyglutamine tracts regulate beclin 1-dependent autophagy.
[So] Source:Nature;545(7652):108-111, 2017 05 04.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.
[Mh] Termos MeSH primário: Ataxina-3/química
Ataxina-3/metabolismo
Autofagia
Beclina-1/metabolismo
Peptídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Ataxina-3/deficiência
Ataxina-3/genética
Ligação Competitiva
Encéfalo/metabolismo
Encéfalo/patologia
Linhagem Celular
Células Cultivadas
Modelos Animais de Doenças
Éxons/genética
Feminino
Privação de Alimentos
Seres Humanos
Proteína Huntingtina/química
Proteína Huntingtina/genética
Proteína Huntingtina/metabolismo
Doença de Huntington/genética
Doença de Huntington/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Proteínas Mutantes/química
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Mutação
Neurônios/citologia
Neurônios/metabolismo
Fagossomos/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Ligação Proteica
Domínios Proteicos
Estabilidade Proteica
Ubiquitina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BECN1 protein, human); 0 (Beclin-1); 0 (HTT protein, human); 0 (Huntingtin Protein); 0 (Mutant Proteins); 0 (Peptides); 0 (Ubiquitin); 26700-71-0 (polyglutamine); EC 3.4.19.12 (Ataxin-3); EC 3.4.19.12 (Atxn3 protein, mouse); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170427
[St] Status:MEDLINE
[do] DOI:10.1038/nature22078


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[PMID]:28374014
[Au] Autor:Tomioka I; Ishibashi H; Minakawa EN; Motohashi HH; Takayama O; Saito Y; Popiel HA; Puentes S; Owari K; Nakatani T; Nogami N; Yamamoto K; Noguchi S; Yonekawa T; Tanaka Y; Fujita N; Suzuki H; Kikuchi H; Aizawa S; Nagano S; Yamada D; Nishino I; Ichinohe N; Wada K; Kohsaka S; Nagai Y; Seki K
[Ad] Endereço:Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
[Ti] Título:Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms.
[So] Source:eNeuro;4(2), 2017 Mar-Apr.
[Is] ISSN:2373-2822
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Age-associated neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3-4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.
[Mh] Termos MeSH primário: Animais Geneticamente Modificados
Callithrix
Modelos Animais de Doenças
Doenças Neurodegenerativas
Peptídeos
[Mh] Termos MeSH secundário: Envelhecimento/patologia
Envelhecimento/fisiologia
Animais
Ataxina-3/genética
Ataxina-3/metabolismo
Encéfalo/diagnóstico por imagem
Encéfalo/metabolismo
Encéfalo/patologia
Linhagem Celular
Progressão da Doença
Orelha
Fibroblastos/metabolismo
Fibroblastos/patologia
Vetores Genéticos
Seres Humanos
Lentivirus/genética
Masculino
Atividade Motora/fisiologia
Músculo Esquelético/metabolismo
Músculo Esquelético/patologia
Doenças Neurodegenerativas/diagnóstico por imagem
Doenças Neurodegenerativas/metabolismo
Doenças Neurodegenerativas/patologia
Peptídeos/metabolismo
Fenótipo
Proteínas Repressoras/genética
Proteínas Repressoras/metabolismo
Expansão das Repetições de Trinucleotídeos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 0 (Repressor Proteins); 26700-71-0 (polyglutamine); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3)
[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:170405
[St] Status:MEDLINE


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[PMID]:28364459
[Au] Autor:Tanaka S; Honda Y; Honda M; Yamada H; Honda K; Kodama T
[Ad] Endereço:Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya, Japan.
[Ti] Título:Anti-Tribbles Pseudokinase 2 (TRIB2)-Immunization Modulates Hypocretin/Orexin Neuronal Functions.
[So] Source:Sleep;40(1), 2017 Jan 01.
[Is] ISSN:1550-9109
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Study Objectives: Recent findings showed that 16%-26% of narcolepsy patients were positive for anti-tribbles pseudokinase 2 (TRIB2) antibody, and the intracerebroventricular administration of immunoglobulin-G purified from anti-TRIB2 positive narcolepsy patients caused hypocretin/orexin neuron loss. We investigated the pathophysiological role of TRIB2 antibody using TRIB2-immunized rats and hypocretin/ataxin-3 transgenic (ataxin-3) mice. Methods: Plasma, cerebrospinal fluid (CSF), and hypothalamic tissues from TRIB2-immunized rats were collected. Anti-TRIB2 titers, hypocretin contents, mRNA expressions, the cell count of hypocretin neurons, and immunoreactivity of anti-TRIB2 antibodies on hypocretin neurons were investigated. The plasma from ataxin-3 mice was also used to determine the anti-TRIB2 antibody titer changes following the loss of hypocretin neurons. Results: TRIB2 antibody titers increased in the plasma and CSF of TRIB2-immunized rats. The hypothalamic tissue immunostained with the sera from TRIB2-immunized rats revealed positive signals in the cytoplasm of hypcretin neurons. While no changes were found regarding hypothalamic hypocretin contents or cell counts, but there were significant decreases of the hypocretin mRNA level and release into the CSF. The plasma from over 26-week-old ataxin-3 mice, at the advanced stage of hypocretin cell destruction, showed positive reactions against TRIB2 antigen, and positive plasma also reacted with murine hypothalamic hypocretin neurons. Conclusions: Our results suggest that the general activation of the immune system modulates the functions of hypocretin neurons. The absence of a change in hypocretin cell populations suggested that factors other than anti-TRIB2 antibody play a part in the loss of hypocretin neurons in narcolepsy. The increased anti-TRIB2 antibody after the destruction of hypocretin neurons suggest that anti-TRIB2 antibody in narcolepsy patients is the consequence rather than the inciting cause of hypocretin cell destruction.
[Mh] Termos MeSH primário: Autoanticorpos/metabolismo
Autoantígenos/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/imunologia
Peptídeos e Proteínas de Sinalização Intracelular/imunologia
Narcolepsia/imunologia
Neurônios/imunologia
Orexinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Ataxina-3/metabolismo
Biomarcadores/metabolismo
Proteínas Quinases Dependentes de Cálcio-Calmodulina/metabolismo
Feminino
Hipotálamo/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Masculino
Camundongos
Camundongos Transgênicos
Narcolepsia/metabolismo
Narcolepsia/fisiopatologia
Neurônios/metabolismo
Neuropeptídeos/metabolismo
Ratos
Ratos Sprague-Dawley
Vacinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (Autoantigens); 0 (Biomarkers); 0 (Intracellular Signaling Peptides and Proteins); 0 (Neuropeptides); 0 (Orexins); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171102
[Lr] Data última revisão:
171102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170402
[St] Status:MEDLINE
[do] DOI:10.1093/sleep/zsw036


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[PMID]:28334907
[Au] Autor:Weber JJ; Golla M; Guaitoli G; Wanichawan P; Hayer SN; Hauser S; Krahl AC; Nagel M; Samer S; Aronica E; Carlson CR; Schöls L; Riess O; Gloeckner CJ; Nguyen HP; Hübener-Schmid J
[Ad] Endereço:Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
[Ti] Título:A combinatorial approach to identify calpain cleavage sites in the Machado-Joseph disease protein ataxin-3.
[So] Source:Brain;140(5):1280-1299, 2017 May 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Ataxin-3, the disease protein in Machado-Joseph disease, is known to be proteolytically modified by various enzymes including two major families of proteases, caspases and calpains. This processing results in the generation of toxic fragments of the polyglutamine-expanded protein. Although various approaches were undertaken to identify cleavage sites within ataxin-3 and to evaluate the impact of fragments on the molecular pathogenesis of Machado-Joseph disease, calpain-mediated cleavage of the disease protein and the localization of cleavage sites remained unclear. Here, we report on the first precise localization of calpain cleavage sites in ataxin-3 and on the characterization of the resulting breakdown products. After confirming the occurrence of calpain-derived fragmentation of ataxin-3 in patient-derived cell lines and post-mortem brain tissue, we combined in silico prediction tools, western blot analysis, mass spectrometry, and peptide overlay assays to identify calpain cleavage sites. We found that ataxin-3 is primarily cleaved at two sites, namely at amino acid positions D208 and S256 and mutating amino acids at both cleavage sites to tryptophan nearly abolished ataxin-3 fragmentation. Furthermore, analysis of calpain cleavage-derived fragments showed distinct aggregation propensities and toxicities of C-terminal polyglutamine-containing breakdown products. Our data elucidate the important role of ataxin-3 proteolysis in the pathogenesis of Machado-Joseph disease and further emphasize the relevance of targeting this disease pathway as a treatment strategy in neurodegenerative disorders.
[Mh] Termos MeSH primário: Ataxina-3/metabolismo
Calpaína/metabolismo
Doença de Machado-Joseph/metabolismo
[Mh] Termos MeSH secundário: Encéfalo/metabolismo
Células Cultivadas
Técnicas de Química Combinatória
Simulação por Computador
Seres Humanos
Células-Tronco Pluripotentes Induzidas/metabolismo
Peptídeo Hidrolases/metabolismo
Agregação Patológica de Proteínas/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.- (Peptide Hydrolases); EC 3.4.19.12 (Ataxin-3); EC 3.4.22.- (Calpain)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx039


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[PMID]:28275011
[Au] Autor:Pfeiffer A; Luijsterburg MS; Acs K; Wiegant WW; Helfricht A; Herzog LK; Minoia M; Böttcher C; Salomons FA; van Attikum H; Dantuma NP
[Ad] Endereço:Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
[Ti] Título:Ataxin-3 consolidates the MDC1-dependent DNA double-strand break response by counteracting the SUMO-targeted ubiquitin ligase RNF4.
[So] Source:EMBO J;36(8):1066-1083, 2017 Apr 13.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The SUMO-targeted ubiquitin ligase RNF4 functions at the crossroads of the SUMO and ubiquitin systems. Here, we report that the deubiquitylation enzyme (DUB) ataxin-3 counteracts RNF4 activity during the DNA double-strand break (DSB) response. We find that ataxin-3 negatively regulates ubiquitylation of the checkpoint mediator MDC1, a known RNF4 substrate. Loss of ataxin-3 markedly decreases the chromatin dwell time of MDC1 at DSBs, which can be fully reversed by co-depletion of RNF4. Ataxin-3 is recruited to DSBs in a SUMOylation-dependent fashion, and it directly interacts with and is stimulated by recombinant SUMO, defining a SUMO-dependent mechanism for DUB activity toward MDC1. Loss of ataxin-3 results in reduced DNA damage-induced ubiquitylation due to impaired MDC1-dependent recruitment of the ubiquitin ligases RNF8 and RNF168, and reduced recruitment of 53BP1 and BRCA1. Finally, ataxin-3 is required for efficient MDC1-dependent DSB repair by non-homologous end-joining and homologous recombination. Consequently, loss of ataxin-3 sensitizes cells to ionizing radiation and poly(ADP-ribose) polymerase inhibitor. We propose that the opposing activities of RNF4 and ataxin-3 consolidate robust MDC1-dependent signaling and repair of DSBs.
[Mh] Termos MeSH primário: Ataxina-3/metabolismo
Quebras de DNA de Cadeia Dupla
Reparo do DNA
Proteínas Nucleares/metabolismo
Proteínas Repressoras/metabolismo
Proteína SUMO-1/metabolismo
Transdução de Sinais
Transativadores/metabolismo
Fatores de Transcrição/metabolismo
[Mh] Termos MeSH secundário: Ataxina-3/genética
Proteína BRCA1/genética
Proteína BRCA1/metabolismo
Cromatina/genética
Cromatina/metabolismo
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Raios gama
Células HEK293
Seres Humanos
Proteínas Nucleares/genética
Proteínas Repressoras/genética
Proteína SUMO-1/genética
Transativadores/genética
Fatores de Transcrição/genética
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética
Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
Ubiquitina-Proteína Ligases/genética
Ubiquitina-Proteína Ligases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BRCA1 Protein); 0 (BRCA1 protein, human); 0 (Chromatin); 0 (DNA-Binding Proteins); 0 (MDC1 protein, human); 0 (Nuclear Proteins); 0 (RNF4 protein, human); 0 (RNF8 protein, human); 0 (Repressor Proteins); 0 (SUMO-1 Protein); 0 (TP53BP1 protein, human); 0 (Trans-Activators); 0 (Transcription Factors); 0 (Tumor Suppressor p53-Binding Protein 1); EC 2.3.2.27 (RNF168 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170310
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201695151


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[PMID]:28236575
[Au] Autor:Carmona V; Cunha-Santos J; Onofre I; Simões AT; Vijayakumar U; Davidson BL; Pereira de Almeida L
[Ad] Endereço:CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Coimbra 3004-504, Portugal; Faculty of Pharmacy, University of Coimbra, Coimbra 3000-548, Portugal.
[Ti] Título:Unravelling Endogenous MicroRNA System Dysfunction as a New Pathophysiological Mechanism in Machado-Joseph Disease.
[So] Source:Mol Ther;25(4):1038-1055, 2017 Apr 05.
[Is] ISSN:1525-0024
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Machado-Joseph disease (MJD) is a genetic neurodegenerative disease caused by an expanded polyglutamine tract within the protein ataxin-3 (ATXN3). Despite current efforts, MJD's mechanism of pathogenesis remains unclear and no disease-modifying treatment is available. Therefore, in this study, we investigated (1) the role of the 3' UTR of ATXN3, a putative microRNA (miRNA) target, (2) whether miRNA biogenesis and machinery are dysfunctional in MJD, and (3) which specific miRNAs target ATXN3-3' UTR and whether they can alleviate MJD neuropathology in vivo. Our results demonstrate that endogenous miRNAs, by targeting sequences in the 3' UTR, robustly reduce ATXN3 expression and aggregation in vitro and neurodegeneration and neuroinflammation in vivo. Importantly, we found an abnormal MJD-associated downregulation of genes involved in miRNA biogenesis and silencing activity. Finally, we identified three miRNAs-mir-9, mir-181a, and mir-494-that interact with the ATXN3-3' UTR and whose expression is dysregulated in human MJD neurons and in other MJD cell and animal models. Furthermore, overexpression of these miRNAs in mice resulted in reduction of mutATXN3 levels, aggregate counts, and neuronal dysfunction. Altogether, these findings indicate that endogenous miRNAs and the 3' UTR of ATXN3 play a crucial role in MJD pathogenesis and provide a promising opportunity for MJD treatment.
[Mh] Termos MeSH primário: Regulação da Expressão Gênica
Doença de Machado-Joseph/genética
MicroRNAs/genética
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Animais
Ataxina-3/genética
Linhagem Celular
Modelos Animais de Doenças
Expressão Gênica
Ordem dos Genes
Genes Reporter
Vetores Genéticos/genética
Seres Humanos
Lentivirus/genética
Doença de Machado-Joseph/metabolismo
Doença de Machado-Joseph/patologia
Camundongos
Camundongos Transgênicos
Mutação
Neurônios/metabolismo
Agregação Patológica de Proteínas
Interferência de RNA
Estabilidade de RNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (MicroRNAs); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE


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[PMID]:28195427
[Au] Autor:Wu C; Chen DB; Feng L; Zhou XX; Zhang JW; You HJ; Liang XL; Pei Z; Li XH
[Ad] Endereço:Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
[Ti] Título:Oculomotor deficits in spinocerebellar ataxia type 3: Potential biomarkers of preclinical detection and disease progression.
[So] Source:CNS Neurosci Ther;23(4):321-328, 2017 Apr.
[Is] ISSN:1755-5949
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIMS: To detect specific oculomotor deficits in preclinical stage of spinocerebellar ataxia type 3 (SCA3) and evaluate whether these abnormalities prove useful as potential biomarkers of disease progression. METHODS: A Chinese cohort of 56 patients with SCA3, including 12 preclinical carriers of SCA3 (pre-SCA3) and 44 manifest SCA3, and 26 healthy control individuals were recruited. We performed a detailed investigation on central oculomotor performance including fixation, gaze, smooth pursuit, prosaccade, and antisaccade using video-oculography. RESULTS: Common oculomotor features of pre-SCA3 included square-wave jerk during central fixation and gaze holding, impaired vertical smooth pursuit, slow upward saccade, and increased antisaccade error rate. In our SCA3 cohort, all oculomotor parameters were correlated with the score of the Scale for the Assessment and Rating of Ataxia, whilst some of them were correlated with disease duration. CONCLUSION: This study showed that a series of neuropathological changes reflected by oculomotor abnormalities appeared preferentially in preclinical stage of SCA3. Accordingly, objective oculomotor preclinical signs may be useful to detect the optimum time-point for therapeutic interventions in future clinical trials of SCA3. Larger and longitudinal data are warranted to confirm our results.
[Mh] Termos MeSH primário: Doença de Machado-Joseph/complicações
Transtornos da Motilidade Ocular/etiologia
[Mh] Termos MeSH secundário: Adulto
Ataxina-3/genética
Progressão da Doença
Feminino
Seres Humanos
Masculino
Entrevista Psiquiátrica Padronizada
Meia-Idade
Mutação/genética
Proteínas Repressoras/genética
Índice de Gravidade de Doença
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Repressor Proteins); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE
[do] DOI:10.1111/cns.12676


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[PMID]:28180282
[Au] Autor:Tu Y; Liu H; Zhu X; Shen H; Ma X; Wang F; Huang M; Gong J; Li X; Wang Y; Guo C; Tang TS
[Ad] Endereço:State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China.
[Ti] Título:Ataxin-3 promotes genome integrity by stabilizing Chk1.
[So] Source:Nucleic Acids Res;45(8):4532-4549, 2017 May 05.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Chk1 protein is essential for genome integrity maintenance and cell survival in eukaryotic cells. After prolonged replication stress, Chk1 can be targeted for proteasomal degradation to terminate checkpoint signaling after DNA repair finishes. To ensure proper activation of DNA damage checkpoint and DNA repair signaling, a steady-state level of Chk1 needs to be retained under physiological conditions. Here, we report a dynamic signaling pathway that tightly regulates Chk1 stability. Under unperturbed conditions and upon DNA damage, ataxin-3 (ATX3) interacts with Chk1 and protects it from DDB1/CUL4A- and FBXO6/CUL1-mediated polyubiquitination and subsequent degradation, thereby promoting DNA repair and checkpoint signaling. Under prolonged replication stress, ATX3 dissociates from Chk1, concomitant with a stronger binding between Chk1 and its E3 ligase, which causes Chk1 proteasomal degradation. ATX3 deficiency results in pronounced reduction of Chk1 abundance, compromised DNA damage response, G2/M checkpoint defect and decreased cell survival after replication stress, which can all be rescued by ectopic expression of ATX3. Taken together, these findings reveal ATX3 to be a novel deubiquitinase of Chk1, providing a new mechanism of Chk1 stabilization in genome integrity maintenance.
[Mh] Termos MeSH primário: Ataxina-3/genética
Quinase do Ponto de Checagem 1/genética
Reparo do DNA
Replicação do DNA
DNA/genética
Pontos de Checagem da Fase G2 do Ciclo Celular/genética
Proteínas Repressoras/genética
[Mh] Termos MeSH secundário: Ataxina-3/metabolismo
Quinase do Ponto de Checagem 1/antagonistas & inibidores
Quinase do Ponto de Checagem 1/metabolismo
Proteínas Culina/genética
Proteínas Culina/metabolismo
DNA/metabolismo
Dano ao DNA
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Genoma Humano
Instabilidade Genômica
Células HEK293
Seres Humanos
Estabilidade Proteica
Proteólise
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Proteínas Repressoras/metabolismo
Proteínas Ligases SKP Culina F-Box/genética
Proteínas Ligases SKP Culina F-Box/metabolismo
Transdução de Sinais
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CUL4A protein, human); 0 (Cullin 1); 0 (Cullin Proteins); 0 (DDB1 protein, human); 0 (DNA-Binding Proteins); 0 (RNA, Small Interfering); 0 (Repressor Proteins); 9007-49-2 (DNA); EC 2.3.2.27 (FBXO6 protein, human); EC 2.3.2.27 (SKP Cullin F-Box Protein Ligases); EC 2.7.11.1 (CHEK1 protein, human); EC 2.7.11.1 (Checkpoint Kinase 1); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170210
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx095



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