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1.
Sci Rep ; 9(1): 11606, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406156

RESUMO

Sporadic inclusion body myositis (sIBM) is the most commonly acquired myopathy in middle-aged and elderly people. The muscle histology is characterized by both inflammation and degeneration, including sarcoplasmic aggregation of TDP-43. Cylindromatosis (CYLD) is a deubiquitinating enzyme that targets Lys63-linked ubiquitin chains and negatively regulates signal transduction pathways, such as NF-κB signalling pathways. We examined localization of CYLD as well as phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in muscle tissues of sIBM patients and muscle-specific wild-type TDP-43 transgenic (TDP-43 TG) mice. We investigated whether overexpression of CYLD can affect muscle toxicity in the cell models treated by endoplasmic reticulum (ER) stress inducers tunicamycin and thapsigargin. CYLD expressed with phosphorylated TDP-43, phosphorylated p62, and Lys63-linked ubiquitin in the nuclear and perinuclear regions of muscle fibres of wild-type TDP-43 TG mice and the degenerative myofibres of sIBM patients with rimmed vacuoles and endomysial cellular infiltration. Although expression levels of CYLD decreased and cell viability was reduced in cells treated with ER stress inducers, wild-type CYLD, but not the catalytic mutant, substantially improved cell viability based on the deubiquitinase activity. Dysregulation of CYLD may reinforce myodegeneration in the pathophysiology of sIBM by attenuating autophagic clearance of protein aggregates. Regulating CYLD in muscle fibres might serve as a novel therapeutic strategy for sIBM treatment.


Assuntos
Enzima Desubiquitinante CYLD/fisiologia , Miosite de Corpos de Inclusão/fisiopatologia , Idoso , Animais , Enzima Desubiquitinante CYLD/genética , Estresse do Retículo Endoplasmático , Humanos , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Miosite de Corpos de Inclusão/metabolismo , Fosforilação , Proteômica , Ubiquitina/metabolismo , Vacúolos/metabolismo
2.
Exp Neurol ; 309: 169-180, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30130494

RESUMO

Muscle histology of sporadic inclusion body myositis (sIBM) demonstrates inflammatory findings and degenerative features including accumulation of TAR DNA-binding protein of 43 kDa (TDP-43). However, whether sarcoplasmic accumulation of TDP-43 is a primary trigger of muscle degeneration or a secondary event resulting from muscle degeneration in the pathophysiology of sIBM remained unclear. Our study aimed to discover whether muscle-dominant expression of TDP-43 is a primary cause of muscle degeneration. We generated several lines of wild-type TDP-43 transgenic mice driven by a creatine kinase 8 promoter, and analyzed the phenotypes via biochemical, histological, and proteomic techniques. The mice showed increased serum levels of myogenic enzymes. Muscle histology demonstrated myopathic changes including fiber size variation, abundant tubular aggregates, and TDP-43 aggregation with upregulation of endoplasmic reticulum (ER) stress. Proteomic analysis with aggregated materials in degenerative myofibers identified increased sarcoplasmic reticulum (SR)/ER-resident proteins that regulated calcium homeostasis, as well as cytosolic 5'-nucleotidase 1A. Muscle-dominant wild-type TDP-43 expression indeed caused myotoxicity featuring tubular aggregates and TDP-43-positive inclusions. Our observation suggested that TDP-43 aggregates might not be sufficient to trigger the pathogenesis of sIBM although myofiber sarcoplasmic aggregation of TDP-43 led to myofiber degeneration via ER stress and possibly calcium dysregulation, independently of inflammatory process.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Miosite de Corpos de Inclusão/metabolismo , Animais , Linhagem Celular Transformada , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/genética , Regulação da Expressão Gênica/genética , Proteínas de Choque Térmico/metabolismo , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica , Músculo Esquelético/patologia , Músculo Esquelético/ultraestrutura , Doenças Musculares/genética , Miosite de Corpos de Inclusão/patologia , Proteômica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transfecção
4.
J Neurol ; 261(11): 2209-17, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25209854

RESUMO

Pathological changes in corticobasal degeneration (CBD) consist of abnormal deposition of the microtubule-associated protein tau. However, the simultaneous accumulation of different misfolded proteins in the brain can be observed in many neurodegenerative diseases with significantly longer disease durations. We encountered a patient with CBD who survived for an extremely long period (18 years) after the diagnosis. We performed an autopsy to elucidate the effect of the longer survival on the pathology of CBD. We observed abnormal aggregation of trans-activating response region DNA-binding protein of 43 kDa (TDP-43) and α-synuclein, as well as phosphorylated tau, in neurons of broader regions of the brain, beyond the amygdala and other limbic areas. We found that phosphorylated tau, α-synuclein, and TDP-43 partially co-existed in the same cellular aggregates. The triple pathologic changes might be related to the longer survival of the patient compared with the typical clinical course of patients with CBD. Further investigations are required to support the hypothesis that tauopathy, synucleinopathy, and TDP-43 proteinopathy might share common pathogenic mechanisms in terms of cross-seeding of the pathologic proteins.


Assuntos
Proteínas de Ligação a DNA/análise , Doenças Neurodegenerativas/diagnóstico , alfa-Sinucleína/análise , Idoso , Córtex Cerebral/química , Córtex Cerebral/patologia , Proteínas de Ligação a DNA/metabolismo , Evolução Fatal , Humanos , Masculino , Doenças Neurodegenerativas/metabolismo , alfa-Sinucleína/metabolismo
5.
J Neurol Sci ; 346(1-2): 133-7, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25152387

RESUMO

BACKGROUND: The incidence of sporadic inclusion body myositis (sIBM) has been much lower in Japanese than in Western populations. Because of a few reports on Asian populations, it is unclear whether the clinical characteristics of sIBM are identical in Caucasian and Japanese patients. METHODS: We compared 18 patients with sIBM, divided into 3 groups by age-of-onset, with previous cohort studies. We calculated the ΔIBM functional rating scale/time duration (ΔIBMFRS/Δtime) as an index of functional disability progression. Patients' electrophysiology was analyzed in relation to their clinical characteristics. RESULTS: The cohort was 83.3% male and showed uniform initial muscle weakness in the lower and/or upper limbs. An older age-at-onset was associated with a more rapid progression, and patients with a longer duration frequently showed F-wave abnormalities and findings of chronic denervation. CONCLUSIONS: The clinical characteristics of sIBM were relatively homogeneous beyond the ethnic differences. Aging might be a synergistic factor for the progression of sIBM pathology.


Assuntos
Extremidades/fisiopatologia , Debilidade Muscular/fisiopatologia , Miosite de Corpos de Inclusão/diagnóstico , Miosite de Corpos de Inclusão/fisiopatologia , Adulto , Idade de Início , Idoso , Povo Asiático , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Miosite de Corpos de Inclusão/complicações , Índice de Gravidade de Doença
6.
Eur Neurol ; 71(3-4): 180-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24457445

RESUMO

BACKGROUND: Nonsystemic vasculitic neuropathy (NSVN) is a vasculitis syndrome clinically restricted to the peripheral nervous system. Although treatment may improve prognosis, daily activities of such patients after treatment have not been well studied. METHODS: We evaluated clinical features, laboratory data, nerve conduction, and sural nerve biopsy findings for 16 unbiased consecutive patients with NSVN. RESULTS: Initial symptoms included neuropathic pain (31%) and lower limb sensory disturbance (19%). The mean duration between disease onset and initial treatment was 4.1 ± 4.8 months. Mean modified Rankin scale scores were 3.13 at hospital admission and 2.69 at final follow-up. The poor outcome group had significantly decreased compound muscle action potentials of peroneal nerves and significantly more patients presenting with foot drop compared with the good outcome group. No other significant differences were found. CONCLUSION: Pretreatment foot drop signaled poor outcome in daily activities of patients with NSVN, and earlier treatment may be critical for these patients.


Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Recuperação de Função Fisiológica , Vasculite/complicações , Atividades Cotidianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologia , Estudos Retrospectivos , Vasculite/tratamento farmacológico , Adulto Jovem
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