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Pesquisa : D12.776.157.725.452.125 [Categoria DeCS]
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[PMID]:28642336
[Au] Autor:Gibson SB; Downie JM; Tsetsou S; Feusier JE; Figueroa KP; Bromberg MB; Jorde LB; Pulst SM
[Ad] Endereço:From the Departments of Neurology (S.B.G., S.T., K.P.F., M.B.B., S.M.P.) and Human Genetics (J.M.D., J.E.F., L.B.J.), University of Utah School of Medicine, Salt Lake City.
[Ti] Título:The evolving genetic risk for sporadic ALS.
[So] Source:Neurology;89(3):226-233, 2017 Jul 18.
[Is] ISSN:1526-632X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)-associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity. METHODS: Whole exome sequencing and repeat expansion PCR of and were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls. RESULTS: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious and 2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls. CONCLUSIONS: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Predisposição Genética para Doença
[Mh] Termos MeSH secundário: Adulto
Ataxina-2/genética
Proteína C9orf72
Estudos de Coortes
Expansão das Repetições de DNA
Grupo com Ancestrais do Continente Europeu/genética
Exoma
Feminino
Frequência do Gene
Seres Humanos
Masculino
Meia-Idade
Modelos Genéticos
Razão de Chances
Análise de Componente Principal
Proteínas/genética
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATXN2 protein, human); 0 (Ataxin-2); 0 (C9orf72 Protein); 0 (C9orf72 protein, human); 0 (Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170624
[St] Status:MEDLINE
[do] DOI:10.1212/WNL.0000000000004109


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[PMID]:28405024
[Au] Autor:Scoles DR; Meera P; Schneider MD; Paul S; Dansithong W; Figueroa KP; Hung G; Rigo F; Bennett CF; Otis TS; Pulst SM
[Ad] Endereço:Department of Neurology, University of Utah, 175 North Medical Drive East, 5th Floor, Salt Lake City, Utah 84132, USA.
[Ti] Título:Antisense oligonucleotide therapy for spinocerebellar ataxia type 2.
[So] Source:Nature;544(7650):362-366, 2017 04 20.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:There are no disease-modifying treatments for adult human neurodegenerative diseases. Here we test RNA-targeted therapies in two mouse models of spinocerebellar ataxia type 2 (SCA2), an autosomal dominant polyglutamine disease. Both models recreate the progressive adult-onset dysfunction and degeneration of a neuronal network that are seen in patients, including decreased firing frequency of cerebellar Purkinje cells and a decline in motor function. We developed a potential therapy directed at the ATXN2 gene by screening 152 antisense oligonucleotides (ASOs). The most promising oligonucleotide, ASO7, downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. These findings support ASOs as a promising approach for treating some human neurodegenerative diseases.
[Mh] Termos MeSH primário: Oligonucleotídeos Antissenso/uso terapêutico
Ataxias Espinocerebelares/genética
Ataxias Espinocerebelares/terapia
[Mh] Termos MeSH secundário: Potenciais de Ação
Animais
Ataxina-2/deficiência
Ataxina-2/genética
Ataxina-2/metabolismo
Modelos Animais de Doenças
Feminino
Regulação da Expressão Gênica
Seres Humanos
Masculino
Camundongos
Camundongos Transgênicos
Movimento
Fenótipo
Células de Purkinje/metabolismo
Células de Purkinje/patologia
RNA Mensageiro/biossíntese
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Teste de Desempenho do Rota-Rod
Ataxias Espinocerebelares/patologia
Ataxias Espinocerebelares/fisiopatologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ATXN2 protein, human); 0 (Ataxin-2); 0 (Atxn2 protein, mouse); 0 (Oligonucleotides, Antisense); 0 (RNA, Messenger)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1038/nature22044


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[PMID]:28405022
[Au] Autor:Becker LA; Huang B; Bieri G; Ma R; Knowles DA; Jafar-Nejad P; Messing J; Kim HJ; Soriano A; Auburger G; Pulst SM; Taylor JP; Rigo F; Gitler AD
[Ad] Endereço:Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
[Ti] Título:Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.
[So] Source:Nature;544(7650):367-371, 2017 04 20.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases. Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression. However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions. Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Esclerose Amiotrófica Lateral/terapia
Ataxina-2/deficiência
Proteínas de Ligação a DNA/metabolismo
Longevidade
Oligonucleotídeos Antissenso/uso terapêutico
Agregação Patológica de Proteínas/terapia
[Mh] Termos MeSH secundário: Esclerose Amiotrófica Lateral/metabolismo
Esclerose Amiotrófica Lateral/fisiopatologia
Animais
Ataxina-2/genética
Sistema Nervoso Central/metabolismo
Grânulos Citoplasmáticos/metabolismo
Proteínas de Ligação a DNA/química
Proteínas de Ligação a DNA/genética
Progressão da Doença
Feminino
Técnicas de Silenciamento de Genes
Seres Humanos
Masculino
Camundongos
Camundongos Knockout
Camundongos Transgênicos
Destreza Motora/fisiologia
Oligonucleotídeos Antissenso/administração & dosagem
Oligonucleotídeos Antissenso/genética
Agregação Patológica de Proteínas/genética
Estresse Fisiológico
Análise de Sobrevida
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ataxin-2); 0 (DNA-Binding Proteins); 0 (Oligonucleotides, Antisense); 0 (TDP-43 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1038/nature22038


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[PMID]:28388438
[Au] Autor:Lee J; Yoo E; Lee H; Park K; Hur JH; Lim C
[Ad] Endereço:School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
[Ti] Título:LSM12 and ME31B/DDX6 Define Distinct Modes of Posttranscriptional Regulation by ATAXIN-2 Protein Complex in Drosophila Circadian Pacemaker Neurons.
[So] Source:Mol Cell;66(1):129-140.e7, 2017 Apr 06.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ATAXIN-2 (ATX2) has been implicated in human neurodegenerative diseases, yet it remains elusive how ATX2 assembles specific protein complexes to execute its physiological roles. Here we employ the posttranscriptional co-activator function of Drosophila ATX2 to demonstrate that LSM12 and ME31B/DDX6 are two ATX2-associating factors crucial for sustaining circadian rhythms. LSM12 acts as a molecular adaptor for the recruitment of TWENTY-FOUR (TYF) to ATX2. The ATX2-LSM12-TYF complex thereby stimulates TYF-dependent translation of the rate-limiting clock gene period (per) to maintain 24 hr periodicity in circadian behaviors. In contrast, ATX2 contributes to NOT1-mediated gene silencing and associates with NOT1 in a ME31B/DDX6-dependent manner. The ME31B/DDX6-NOT1 complex does not affect PER translation but supports high-amplitude behavioral rhythms along with ATX2, indicating a PER-independent clock function of ATX2. Taken together, these data suggest that the ATX2 complex may switch distinct modes of posttranscriptional regulation through its associating factors to control circadian clocks and ATX2-related physiology.
[Mh] Termos MeSH primário: Ataxina-2/metabolismo
Comportamento Animal
Relógios Circadianos
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo
Ritmo Circadiano
RNA Helicases DEAD-box/metabolismo
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/enzimologia
Locomoção
Neurônios/enzimologia
Interferência de RNA
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Ataxina-2/genética
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Linhagem Celular
Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética
RNA Helicases DEAD-box/genética
Proteínas de Drosophila/genética
Drosophila melanogaster/citologia
Drosophila melanogaster/genética
Genótipo
Complexos Multiproteicos
Mutação
Proteínas Circadianas Period/genética
Proteínas Circadianas Period/metabolismo
Fenótipo
Transdução de Sinais
Fatores de Tempo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATX2 protein, Drosophila); 0 (Ataxin-2); 0 (Carrier Proteins); 0 (Circadian Rhythm Signaling Peptides and Proteins); 0 (Drosophila Proteins); 0 (LSM12 protein, Drosophila); 0 (Multiprotein Complexes); 0 (NOT1 protein, Drosophila); 0 (PER protein, Drosophila); 0 (Period Circadian Proteins); 0 (twenty-four protein, Drosophila); EC 2.7.7.- (Me31B protein, Drosophila); EC 3.6.4.13 (DEAD-box RNA Helicases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE


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[PMID]:28017481
[Au] Autor:Sproviero W; Shatunov A; Stahl D; Shoai M; van Rheenen W; Jones AR; Al-Sarraj S; Andersen PM; Bonini NM; Conforti FL; Van Damme P; Daoud H; Del Mar Amador M; Fogh I; Forzan M; Gaastra B; Gellera C; Gitler AD; Hardy J; Fratta P; La Bella V; Le Ber I; Van Langenhove T; Lattante S; Lee YC; Malaspina A; Meininger V; Millecamps S; Orrell R; Rademakers R; Robberecht W; Rouleau G; Ross OA; Salachas F; Sidle K; Smith BN; Soong BW; Sorarù G; Stevanin G; Kabashi E; Troakes C; van Broeckhoven C; Veldink JH; van den Berg LH; Shaw CE; Powell JF; Al-Chalabi A
[Ad] Endereço:Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
[Ti] Título:ATXN2 trinucleotide repeat length correlates with risk of ALS.
[So] Source:Neurobiol Aging;51:178.e1-178.e9, 2017 Mar.
[Is] ISSN:1558-1497
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10 ), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.
[Mh] Termos MeSH primário: Esclerose Amiotrófica Lateral/genética
Ataxina-2/genética
Estudos de Associação Genética
Expansão das Repetições de Trinucleotídeos/genética
Repetições de Trinucleotídeos/genética
[Mh] Termos MeSH secundário: Idade de Início
Alelos
Estudos de Casos e Controles
Feminino
Seres Humanos
Masculino
Risco
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS
[Nm] Nome de substância:
0 (ATXN2 protein, human); 0 (Ataxin-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161227
[St] Status:MEDLINE


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[PMID]:28017238
[Au] Autor:Almaguer-Mederos LE; Almaguer-Gotay D; Aguilera-Rodríguez R; González-Zaldívar Y; Cuello-Almarales D; Laffita-Mesa J; Vázquez-Mojena Y; Zayas-Feria P; Rodríguez-Labrada R; Velázquez-Pérez L; MacLeod P
[Ad] Endereço:Center for the Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguín, Cuba. Electronic address: leam@cristal.hlg.sld.cu.
[Ti] Título:Association of glutathione S-transferase omega polymorphism and spinocerebellar ataxia type 2.
[So] Source:J Neurol Sci;372:324-328, 2017 Jan 15.
[Is] ISSN:1878-5883
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Spinocerebellar ataxia type 2 is a neurodegenerative disorder caused by a CAG repeat expansion in ATXN2 gene. There is high clinical variability among affected patients suggesting the occurring of modifier genes influencing the clinical phenotype. OBJECTIVE: The objective is to assess the association of GSTO1 rs4925 and GSTO2 rs2297235 SNPs on the clinical phenotype in SCA2 patients. METHODS: A case-control study was performed in a sample of 120 SCA2 Cuban patients and 100 healthy subjects. Age at onset, 60° Maximal Saccade Velocity and SARA score were used as clinical markers. GSTO1 rs4925 and GSTO2 rs2297235 SNPs were determined by PCR/RFLP. RESULTS: Distribution of the GSTO1 alleles and genotypes was nearly equal between the control group and SCA2 patients. GSTO1 genotypes were not associated to clinical markers in SCA2 patients. Distribution of the GSTO2 "G" allele and "AG" genotype differed significantly between SCA2 patients and controls. Symptomatic SCA2 individuals had a 2.29-fold higher chance of carrying at least one "G" allele at GSTO2 rs2297235 than controls (OR=2.29, 95% CI: 1.29-4.04). GSTO2 genotypes were significantly associated to age at onset (p=0.037) but not to 60° Maximal Saccade Velocity or SARA score in SCA2 patients. CONCLUSION: The GSTO1 rs4925 polymorphism is not associated to SCA2. Meanwhile, the GSTO2 rs2297235 "AG" genotype is associated to SCA2 but failed to show any association with clinical markers, with the exception of a potential association with the age at disease onset.
[Mh] Termos MeSH primário: Predisposição Genética para Doença/genética
Glutationa Transferase/genética
Polimorfismo de Nucleotídeo Único/genética
Ataxias Espinocerebelares/genética
[Mh] Termos MeSH secundário: Idade de Início
Ataxina-2/genética
Estudos de Casos e Controles
Biologia Computacional
Feminino
Frequência do Gene
Estudos de Associação Genética
Genótipo
Seres Humanos
Modelos Lineares
Masculino
Movimentos Sacádicos/genética
Índice de Gravidade de Doença
Repetições de Trinucleotídeos/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ataxin-2); EC 2.5.1.18 (GSTO1 protein, human); EC 2.5.1.18 (GSTO2 protein, human); EC 2.5.1.18 (Glutathione Transferase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161227
[St] Status:MEDLINE


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[PMID]:27730516
[Au] Autor:Velázquez-Pérez L; Tünnerhoff J; Rodríguez-Labrada R; Torres-Vega R; Belardinelli P; Medrano-Montero J; Peña-Acosta A; Canales-Ochoa N; Vázquez-Mojena Y; González-Zaldivar Y; Auburger G; Ziemann U
[Ad] Endereço:Department Clinical Neurophysiology, Centre for the Research and Rehabilitation of Hereditary Ataxias, Calle Libertad 26, Holguín, Cuba, 80100. luis.velazquez@infomed.sld.cu.
[Ti] Título:Corticomuscular Coherence: a Novel Tool to Assess the Pyramidal Tract Dysfunction in Spinocerebellar Ataxia Type 2.
[So] Source:Cerebellum;16(2):602-606, 2017 Apr.
[Is] ISSN:1473-4230
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Clinical signs of corticospinal tract dysfunction are a common feature of spinocerebellar ataxia type 2 (SCA2) patients. The objective of this study is to assess dysfunction of the corticospinal tract in SCA2 using corticomuscular coherence. Testing corticomuscular coherence and rating of ataxia severity and non-ataxia symptoms were performed in 19 SCA2 patients and 24 age-matched controls. Central motor conduction times (CMCT) to upper and lower right limbs were obtained for the SCA2 group using Transcraneal magnetic stimulation (TMS). SCA2 patients exhibited a significant reduction of corticomuscular coherence for lower limbs, but not for upper limbs. This difference remained significant, even when excluding those individuals with clinical signs of corticospinal tract dysfunction. Corticomuscular coherence for lower limbs correlated inversely with CMCT to tibialis anterior muscle. Corticomuscular coherence could be a valuable electrophysiological tool to assess the corticospinal tract involvement in SCA2, even in the absence of clinical signs of corticospinal tract dysfunction.
[Mh] Termos MeSH primário: Eletroencefalografia
Eletromiografia
Músculo Esquelético/fisiopatologia
Tratos Piramidais/fisiopatologia
Ataxias Espinocerebelares/diagnóstico
Ataxias Espinocerebelares/fisiopatologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Ataxina-2/genética
Feminino
Seres Humanos
Extremidade Inferior/fisiopatologia
Masculino
Meia-Idade
Mutação
Condução Nervosa/fisiologia
Índice de Gravidade de Doença
Processamento de Sinais Assistido por Computador
Ataxias Espinocerebelares/genética
Estimulação Magnética Transcraniana
Extremidade Superior/fisiopatologia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ATXN2 protein, human); 0 (Ataxin-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171110
[Lr] Data última revisão:
171110
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161013
[St] Status:MEDLINE
[do] DOI:10.1007/s12311-016-0827-4


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[PMID]:26868665
[Au] Autor:Halbach MV; Gispert S; Stehning T; Damrath E; Walter M; Auburger G
[Ad] Endereço:Experimental Neurology, Department of Neurology, Goethe University Medical School, Building 89, 3rd floor, Theodor Stern Kai 7, 60590, Frankfurt am Main, Germany.
[Ti] Título:Atxn2 Knockout and CAG42-Knock-in Cerebellum Shows Similarly Dysregulated Expression in Calcium Homeostasis Pathway.
[So] Source:Cerebellum;16(1):68-81, 2017 Feb.
[Is] ISSN:1473-4230
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disorder with preferential affection of Purkinje neurons, which are known as integrators of calcium currents. The expansion of a polyglutamine (polyQ) domain in the RNA-binding protein ataxin-2 (ATXN2) is responsible for this disease, but the causal roles of deficient ATXN2 functions versus aggregation toxicity are still under debate. Here, we studied mouse mutants with Atxn2 knockout (KO) regarding their cerebellar global transcriptome by microarray and RT-qPCR, in comparison with data from Atxn2-CAG42-knock-in (KIN) mouse cerebellum. Global expression downregulations involved lipid and growth signaling pathways in good agreement with previous data. As a novel effect, downregulations of key factors in calcium homeostasis pathways (the transcription factor Rora, transporters Itpr1 and Atp2a2, as well as regulator Inpp5a) were observed in the KO cerebellum, and some of them also occurred subtly early in KIN cerebellum. The ITPR1 protein levels were depleted from soluble fractions of cerebellum in both mutants, but accumulated in its membrane-associated form only in the SCA2 model. Coimmunoprecipitation demonstrated no association of ITPR1 with Q42-expanded or with wild-type ATXN2. These findings provide evidence that the physiological functions and protein interactions of ATXN2 are relevant for calcium-mediated excitation of Purkinje cells as well as for ATXN2-triggered neurotoxicity. These insights may help to understand pathogenesis and tissue specificity in SCA2 and other polyQ ataxias like SCA1, where inositol regulation of calcium flux and RORalpha play a role.
[Mh] Termos MeSH primário: Ataxina-2/genética
Ataxina-2/metabolismo
Cálcio/metabolismo
Cerebelo/metabolismo
Homeostase/fisiologia
Transcriptoma
[Mh] Termos MeSH secundário: Animais
Cerebelo/patologia
Expressão Gênica/fisiologia
Técnicas de Introdução de Genes
Técnicas de Inativação de Genes
Receptores de Inositol 1,4,5-Trifosfato/metabolismo
Camundongos da Linhagem 129
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Células de Purkinje/metabolismo
Células de Purkinje/patologia
Transcriptoma/fisiologia
Repetições de Trinucleotídeos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ataxin-2); 0 (Atxn2 protein, mouse); 0 (Inositol 1,4,5-Trisphosphate Receptors); 0 (Itpr1 protein, mouse); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160213
[St] Status:MEDLINE
[do] DOI:10.1007/s12311-016-0762-4


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[PMID]:26861241
[Au] Autor:Wen J; Scoles DR; Facelli JC
[Ad] Endereço:a Department of Biomedical Informatics , University of Utah , Salt Lake City , UT , USA.
[Ti] Título:Effects of the enlargement of polyglutamine segments on the structure and folding of ataxin-2 and ataxin-3 proteins.
[So] Source:J Biomol Struct Dyn;35(3):504-519, 2017 Feb.
[Is] ISSN:1538-0254
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3) are two common autosomal-dominant inherited ataxia syndromes, both of which are related to the unstable expansion of trinucleotide CAG repeats in the coding region of the related ATXN2 and ATXN3 genes, respectively. The poly-glutamine (poly-Q) tract encoded by the CAG repeats has long been recognized as an important factor in disease pathogenesis and progress. In this study, using the I-TASSER method for 3D structure prediction, we investigated the effect of poly-Q tract enlargement on the structure and folding of ataxin-2 and ataxin-3 proteins. Our results show good agreement with the known experimental structures of the Josephin and UIM domains providing credence to the simulation results presented here, which show that the enlargement of the poly-Q region not only affects the local structure of these regions but also affects the structures of functional domains as well as the whole protein. The changes observed in the predicted models of the UIM domains in ataxin-3 when the poly-Q track is enlarged provide new insights on possible pathogenic mechanisms.
[Mh] Termos MeSH primário: Ataxina-2/química
Ataxina-3/química
Modelos Moleculares
Peptídeos/química
Conformação Proteica
Dobramento de Proteína
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas de Transporte/química
Sequência Conservada
Peptídeos/farmacologia
Matrizes de Pontuação de Posição Específica
Ligação Proteica
Domínios Proteicos
Dobramento de Proteína/efeitos dos fármacos
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ataxin-2); 0 (Carrier Proteins); 0 (Peptides); 26700-71-0 (polyglutamine); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170903
[Lr] Data última revisão:
170903
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160211
[St] Status:MEDLINE
[do] DOI:10.1080/07391102.2016.1152199


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[PMID]:27559134
[Au] Autor:Gnazzo MM; Uhlemann EE; Villarreal AR; Shirayama M; Dominguez EG; Skop AR
[Ad] Endereço:Laboratory of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706.
[Ti] Título:The RNA-binding protein ATX-2 regulates cytokinesis through PAR-5 and ZEN-4.
[So] Source:Mol Biol Cell;27(20):3052-3064, 2016 Oct 15.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The spindle midzone harbors both microtubules and proteins necessary for furrow formation and the completion of cytokinesis. However, the mechanisms that mediate the temporal and spatial recruitment of cell division factors to the spindle midzone and midbody remain unclear. Here we describe a mechanism governed by the conserved RNA-binding protein ATX-2/Ataxin-2, which targets and maintains ZEN-4 at the spindle midzone. ATX-2 does this by regulating the amount of PAR-5 at mitotic structures, particularly the spindle, centrosomes, and midbody. Preventing ATX-2 function leads to elevated levels of PAR-5, enhanced chromatin and centrosome localization of PAR-5-GFP, and ultimately a reduction of ZEN-4-GFP at the spindle midzone. Codepletion of ATX-2 and PAR-5 rescued the localization of ZEN-4 at the spindle midzone, indicating that ATX-2 mediates the localization of ZEN-4 upstream of PAR-5. We provide the first direct evidence that ATX-2 is necessary for cytokinesis and suggest a model in which ATX-2 facilitates the targeting of ZEN-4 to the spindle midzone by mediating the posttranscriptional regulation of PAR-5.
[Mh] Termos MeSH primário: Ataxina-2/metabolismo
Ataxina-2/fisiologia
Citocinese/fisiologia
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans/metabolismo
Proteínas de Caenorhabditis elegans/metabolismo
Centrossomo/metabolismo
Cinesina/metabolismo
Proteínas Associadas aos Microtúbulos/metabolismo
Microtúbulos/metabolismo
Mitose
RNA/metabolismo
Proteínas de Ligação a RNA/metabolismo
Fuso Acromático/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ataxin-2); 0 (Caenorhabditis elegans Proteins); 0 (FTT-1 protein, C elegans); 0 (Microtubule-Associated Proteins); 0 (RNA-Binding Proteins); 0 (ZEN-4 protein, C elegans); 63231-63-0 (RNA); EC 3.6.4.4 (Kinesin)
[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:160826
[St] Status:MEDLINE



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