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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


  2 / 712 MEDLINE  
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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


  3 / 712 MEDLINE  
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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


  4 / 712 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


  5 / 712 MEDLINE  
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[PMID]:28158474
[Au] Autor:Sutton JR; Blount JR; Libohova K; Tsou WL; Joshi GS; Paulson HL; Costa MDC; Scaglione KM; Todi SV
[Ad] Endereço:Department of Pharmacology, Wayne State University, Detroit MI, USA.
[Ti] Título:Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.
[So] Source:Hum Mol Genet;26(8):1419-1431, 2017 Apr 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Polyglutamine (polyQ) repeat expansion in the deubiquitinase ataxin-3 causes neurodegeneration in Spinocerebellar Ataxia Type 3 (SCA3), one of nine inherited, incurable diseases caused by similar mutations. Ataxin-3's degradation is inhibited by its binding to the proteasome shuttle Rad23 through ubiquitin-binding site 2 (UbS2). Disrupting this interaction decreases levels of ataxin-3. Since reducing levels of polyQ proteins can decrease their toxicity, we tested whether genetically modulating the ataxin-3-Rad23 interaction regulates its toxicity in Drosophila. We found that exogenous Rad23 increases the toxicity of pathogenic ataxin-3, coincident with increased levels of the disease protein. Conversely, reducing Rad23 levels alleviates toxicity in this SCA3 model. Unexpectedly, pathogenic ataxin-3 with a mutated Rad23-binding site at UbS2, despite being present at markedly lower levels, proved to be more pathogenic than a disease-causing counterpart with intact UbS2. Additional studies established that the increased toxicity upon mutating UbS2 stems from disrupting the autoprotective role that pathogenic ataxin-3 has against itself, which depends on the co-chaperone, DnaJ-1. Our data reveal a previously unrecognized balance between pathogenic and potentially therapeutic properties of the ataxin-3-Rad23 interaction; they highlight this interaction as critical for the toxicity of the SCA3 protein, and emphasize the importance of considering protein context when pursuing suppressive avenues.
[Mh] Termos MeSH primário: Ataxina-3/genética
Enzimas Reparadoras do DNA/genética
Proteínas de Ligação a DNA/genética
Doença de Machado-Joseph/genética
Degeneração Neural/genética
Proteínas Repressoras/genética
[Mh] Termos MeSH secundário: Animais
Ataxina-3/metabolismo
Sítios de Ligação
Enzimas Reparadoras do DNA/metabolismo
Proteínas de Ligação a DNA/metabolismo
Modelos Animais de Doenças
Drosophila melanogaster/genética
Seres Humanos
Doença de Machado-Joseph/metabolismo
Doença de Machado-Joseph/patologia
Chaperonas Moleculares/genética
Degeneração Neural/patologia
Peptídeos/genética
Complexo de Endopeptidases do Proteassoma/genética
Complexo de Endopeptidases do Proteassoma/metabolismo
Ligação Proteica
Proteínas Repressoras/metabolismo
Ubiquitina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Molecular Chaperones); 0 (Peptides); 0 (Repressor Proteins); 0 (Ubiquitin); 156533-33-4 (RAD23A protein, human); 26700-71-0 (polyglutamine); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 6.5.1.- (DNA Repair Enzymes)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170204
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx039


  6 / 712 MEDLINE  
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[PMID]:28032667
[Au] Autor:Gonçalves N; Simões AT; Prediger RD; Hirai H; Cunha RA; Pereira de Almeida L
[Ad] Endereço:Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
[Ti] Título:Caffeine alleviates progressive motor deficits in a transgenic mouse model of spinocerebellar ataxia.
[So] Source:Ann Neurol;81(3):407-418, 2017 Mar.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Machado-Joseph disease (MJD) is a neurodegenerative spinocerebellar ataxia (SCA) associated with an expanded polyglutamine tract within ataxin-3 for which there is currently no available therapy. We previously showed that caffeine, a nonselective adenosine receptor antagonist, delays the appearance of striatal damage resulting from expression of full-length mutant ataxin-3. Here we investigated the ability of caffeine to alleviate behavioral deficits and cerebellar neuropathology in transgenic mice with a severe ataxia resulting from expression of a truncated fragment of polyglutamine-expanded ataxin-3 in Purkinje cells. METHODS: Control and transgenic c57Bl6 mice expressing in the mouse cerebella a truncated form of human ataxin-3 with 69 glutamine repeats were allowed to freely drink water or caffeinated water (1g/L). Treatments began at 7 weeks of age, when motor and ataxic phenotype emerges in MJD mice, and lasted up to 20 weeks. Mice were tested in a panel of locomotor behavioral paradigms, namely rotarod, beam balance and walking, pole, and water maze cued-platform version tests, and then sacrificed for cerebellar histology. RESULTS: Caffeine consumption attenuated the progressive loss of general and fine-tuned motor function, balance, and grip strength, in parallel with preservation of cerebellar morphology through decreasing the loss of Purkinje neurons and the thinning of the molecular layer in different folia. Caffeine also rescued the putative striatal-dependent executive and cognitive deficiencies in MJD mice. INTERPRETATION: Our findings provide the first in vivo demonstration that caffeine intake alleviates behavioral disabilities in a severely impaired animal model of SCA. Ann Neurol 2017;81:407-418.
[Mh] Termos MeSH primário: Comportamento Animal
Cafeína/farmacologia
Doença de Machado-Joseph/tratamento farmacológico
Antagonistas de Receptores Purinérgicos P1/farmacologia
[Mh] Termos MeSH secundário: Animais
Ataxina-3/genética
Comportamento Animal/efeitos dos fármacos
Cafeína/administração & dosagem
Modelos Animais de Doenças
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Antagonistas de Receptores Purinérgicos P1/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Purinergic P1 Receptor Antagonists); 3G6A5W338E (Caffeine); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170630
[Lr] Data última revisão:
170630
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161230
[St] Status:MEDLINE
[do] DOI:10.1002/ana.24867


  7 / 712 MEDLINE  
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[PMID]:27491321
[Au] Autor:Wolf AE; Mourão L; França MC; Machado Júnior AJ; Crespo AN
[Ad] Endereço:School of Medicine Ribeirão Preto, USP Ribeirão Preto, Ribeirão Preto, Brazil.
[Ti] Título:Phonoarticulation in spinocerebellar ataxia type 3.
[So] Source:Eur Arch Otorhinolaryngol;274(2):1139-1145, 2017 02.
[Is] ISSN:1434-4726
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Phonoarticulation is characterized by changes in resonance, diadochokinesis, prosody, sound frequency, vocal quality, and intraoral pressure. The main aim of this study was to characterize the phonoarticulation in spinocerebellar ataxia type 3 (SCA3) and correlate it with clinical and genetic factors. Thirty-one patients with SCA3 who were subjected to spontaneous speech recordings and phonoarticulatory diadochokinesis (DDK) participated in the study. Speech analyses were performed starting after 10 s of spontaneous speech, by three experienced speech therapists, using a protocol for dysarthria adapted from the Mayo Clinic. The intra-evaluator reliability was analyzed. The lower the patient's age at disease onset was, the more frequent the occurrences of monofrequency and altered speech rhythm were. Articulation, DDK, resonance, and prosody showed a moderate correlation with the number of "CAG" triplet repeats. We conclude that the phonoarticulation of patients with Machado-Joseph disease (MJD) is characterized by mixed dysarthrophonia with cerebellar and hypokinetic components, and that there is a tendency toward higher frequency of dysarthrophonia symptoms with lower age of disease onset, longer time since onset and higher number of "CAG" triplet repeats.
[Mh] Termos MeSH primário: Disartria/etiologia
Doença de Machado-Joseph/complicações
Transtorno Fonológico/etiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idade de Início
Idoso
Disartria/diagnóstico
Disartria/genética
Feminino
Seres Humanos
Doença de Machado-Joseph/genética
Masculino
Meia-Idade
Variações Dependentes do Observador
Reprodutibilidade dos Testes
Testes de Articulação da Fala
Transtorno Fonológico/diagnóstico
Transtorno Fonológico/genética
Repetições de Trinucleotídeos
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160806
[St] Status:MEDLINE
[do] DOI:10.1007/s00405-016-4240-x


  8 / 712 MEDLINE  
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[PMID]:27021342
[Au] Autor:Martinez AR; Nunes MB; Faber I; D'Abreu A; Lopes-Cendes Í; França MC
[Ad] Endereço:Department of Neurology, University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo, 126, Cidade Universitaria "Zeferino Vaz", Campinas, São Paulo, 13083-970, Brazil.
[Ti] Título:Fatigue and Its Associated Factors in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.
[So] Source:Cerebellum;16(1):118-121, 2017 Feb.
[Is] ISSN:1473-4230
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fatigue has been described in several neurodegenerative diseases, reducing quality of life. A systematic evaluation of this clinical feature is lacking in SCA3/MJD. The aim of this study was to evaluate the frequency and the factors associated with fatigue in SCA3/MJD. Patients with SCA3/MJD and matched healthy controls answered the Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Scale for the assessment and rating of ataxia (SARA) was used to determine ataxia severity. We used Mann-Whitney and Fisher exact tests to compare mean scores and proportions between groups. Linear regression analyses were employed to investigate factors associated with fatigue in SCA3/MJD. Seventy-four patients were included with a mean age and disease duration of 47.2 ± 12.8 and 9.5 ± 6.37 years, respectively. There were 38 men and 36 women. Mean (CAG)n was 72.2 ± 3.8. Mean MFIS score was higher in patients with SCA3/MJD (41.4 ± 16.2 vs 18.4 ± 12.9, p < 0.001). According to BDI scores, relevant depressive symptoms were found in 69.4 % of patients but only in 10.4 % of controls (p < 0.001). The proportion of patients with ESS scores indicating excessive daytime somnolence was also higher than controls (37.5 vs 22.3 %, p = 0.05). In the multiple regression analysis, both BDI and ESS scores were associated with fatigue (r = 0.67, p < 0.001 and p = 0.01). Fatigue is frequent and strongly associated with depression and excessive daytime somnolence in SCA3/MJD.
[Mh] Termos MeSH primário: Fadiga/complicações
Fadiga/fisiopatologia
Doença de Machado-Joseph/complicações
Doença de Machado-Joseph/fisiopatologia
[Mh] Termos MeSH secundário: Ataxia/complicações
Ataxia/fisiopatologia
Depressão/complicações
Depressão/fisiopatologia
Fadiga/psicologia
Feminino
Seres Humanos
Modelos Lineares
Doença de Machado-Joseph/psicologia
Masculino
Meia-Idade
Escalas de Graduação Psiquiátrica
Índice de Gravidade de Doença
[Pt] Tipo de publicação:JOURNAL ARTICLE
[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:160330
[St] Status:MEDLINE
[do] DOI:10.1007/s12311-016-0775-z


  9 / 712 MEDLINE  
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[PMID]:27878228
[Au] Autor:Lopes-Ramos CM; Pereira TC; Dogini DB; Gilioli R; Lopes-Cendes I
[Ad] Endereço:Departamento de Genética Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil.
[Ti] Título:Lithium carbonate and coenzyme Q10 reduce cell death in a cell model of Machado-Joseph disease.
[So] Source:Braz J Med Biol Res;49(12):e5805, 2016 Nov 21.
[Is] ISSN:1414-431X
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by expansion of the polyglutamine domain of the ataxin-3 (ATX3) protein. MJD/SCA3 is the most frequent autosomal dominant ataxia in many countries. The mechanism underlying MJD/SCA3 is thought to be mainly related to protein misfolding and aggregation leading to neuronal dysfunction followed by cell death. Currently, there are no effective treatments for patients with MJD/SCA3. Here, we report on the potential use of lithium carbonate and coenzyme Q10 to reduce cell death caused by the expanded ATX3 in cell culture. Cell viability and apoptosis were evaluated by MTT assay and by flow cytometry after staining with annexin V-FITC/propidium iodide. Treatment with lithium carbonate and coenzyme Q10 led to a significant increase in viability of cells expressing expanded ATX3 (Q84). In addition, we found that the increase in cell viability resulted from a significant reduction in the proportion of apoptotic cells. Furthermore, there was a significant change in the expanded ATX3 monomer/aggregate ratio after lithium carbonate and coenzyme Q10 treatment, with an increase in the monomer fraction and decrease in aggregates. The safety and tolerance of both drugs are well established; thus, our results indicate that lithium carbonate and coenzyme Q10 are good candidates for further in vivo therapeutic trials.
[Mh] Termos MeSH primário: Ataxina-3/efeitos dos fármacos
Morte Celular/efeitos dos fármacos
Carbonato de Lítio/farmacologia
Doença de Machado-Joseph
Proteínas Repressoras/efeitos dos fármacos
Ubiquinona/análogos & derivados
[Mh] Termos MeSH secundário: Diferenciação Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Doença de Machado-Joseph/tratamento farmacológico
Ubiquinona/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Repressor Proteins); 1339-63-5 (Ubiquinone); 2BMD2GNA4V (Lithium Carbonate); EC 3.4.19.12 (ATXN3 protein, human); EC 3.4.19.12 (Ataxin-3); EJ27X76M46 (coenzyme Q10)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161124
[St] Status:MEDLINE


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[PMID]:27851749
[Au] Autor:Liu H; Li X; Ning G; Zhu S; Ma X; Liu X; Liu C; Huang M; Schmitt I; Wüllner U; Niu Y; Guo C; Wang Q; Tang TS
[Ad] Endereço:State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
[Ti] Título:The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53.
[So] Source:PLoS Biol;14(11):e2000733, 2016 Nov.
[Is] ISSN:1545-7885
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish. Furthermore, the polyglutamine (polyQ)-expanded ATX-3 retains enhanced interaction and deubiquitination catalytic activity to p53 and causes more severe p53-dependent neurodegeneration in zebrafish brains and in the substantia nigra pars compacta (SNpc) or striatum of a transgenic SCA3 mouse model. Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis.
[Mh] Termos MeSH primário: Apoptose
Ataxina-3/metabolismo
Doença de Machado-Joseph/enzimologia
Proteína Supressora de Tumor p53/metabolismo
[Mh] Termos MeSH secundário: Animais
Camundongos
Estabilidade Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Tumor Suppressor Protein p53); EC 3.4.19.12 (Ataxin-3)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170524
[Lr] Data última revisão:
170524
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161117
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pbio.2000733



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