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1.
Cell Biol Toxicol ; 40(1): 48, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38900277

RESUMO

Aggregation of aberrant proteins is a common pathological hallmark in neurodegeneration such as polyglutamine (polyQ) and other repeat-expansion diseases. Here through overexpression of ataxin3 C-terminal polyQ expansion in Drosophila gut enterocytes, we generated an intestinal obstruction model of spinocerebellar ataxia type3 (SCA3) and reported a new role of nuclear-associated endosomes (NAEs)-the delivery of polyQ to the nucleoplasm. In this model, accompanied by the prominently increased RAB5-positive NAEs are abundant nucleoplasmic reticulum enriched with polyQ, abnormal nuclear envelope invagination, significantly reduced endoplasmic reticulum, indicating dysfunctional nucleocytoplasmic trafficking and impaired endomembrane organization. Consistently, Rab5 but not Rab7 RNAi further decreased polyQ-related NAEs, inhibited endomembrane disorganization, and alleviated disease model. Interestingly, autophagic proteins were enriched in polyQ-related NAEs and played non-canonical autophagic roles as genetic manipulation of autophagic molecules exhibited differential impacts on NAEs and SCA3 toxicity. Namely, the down-regulation of Atg1 or Atg12 mitigated while Atg5 RNAi aggravated the disease phenotypes both in Drosophila intestines and compound eyes. Our findings, therefore, provide new mechanistic insights and underscore the fundamental roles of endosome-centered nucleocytoplasmic trafficking and homeostatic endomembrane allocation in the pathogenesis of polyQ diseases.


Assuntos
Autofagia , Endossomos , Peptídeos , Animais , Peptídeos/metabolismo , Endossomos/metabolismo , Núcleo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Transporte Ativo do Núcleo Celular , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Doença de Machado-Joseph/metabolismo , Doença de Machado-Joseph/genética , Doença de Machado-Joseph/patologia , Enterócitos/metabolismo , Modelos Animais de Doenças , Ataxina-3/metabolismo , Ataxina-3/genética , Drosophila/metabolismo
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 27(5): 497-500, 2010 Oct.
Artigo em Zh | MEDLINE | ID: mdl-20931524

RESUMO

OBJECTIVE: To report an X-linked dominant Charcot-Marie-Tooth disease (CMTX) Chinese family with vocal cord paresis and to identify the mutation of gap junction protein beta 1 gene (GJB1). METHODS: Part of the family members with dysphagia, dysphonia and lethal respiratory failure were studied through flexible laryngoscope, clinical, brain MRI and electrophysiological examinations. After excluding large fragment tandem duplication containing peripheral myelin protein 22 gene (PMP22), direct sequencing was performed to analyze the mutation of the GJB1 gene in 5 patients including the proband, 5 unaffected family members and 50 unrelated healthy individuals. RESULTS: Eight members spanning 3 generations in this family were affected with CMTX characterized by progressive atrophy and weakness of the anterior tibial and peroneal muscles, especially in the proband. Vocal cord paresis was observed through flexible laryngoscope in total of 4 affected members with dysarthria and dysphagia, 2 of them died of severe respiratory failure due to complete bilateral vocal cord involvement. Normal brain MRI was observed in the proband. The electrophysiological data showed predominant demyelization involving the motor and sensory nerves in the proband. DNA sequencing revealed a de novo c.186 C>G missense mutation in exon 2 of the GJB1 gene, the mutation cosegregated with phenotype. CONCLUSION: Respiratory failure associated with vocal cord involvement may be a rare and severe symptom in CMTX. The present report provides further evidence for clinical and genetic heterogeneity in the X-linked Charcot-Marie-Tooth disease.


Assuntos
Povo Asiático/genética , Doença de Charcot-Marie-Tooth/genética , Conexinas/genética , Mutação de Sentido Incorreto , Paralisia das Pregas Vocais/genética , Adolescente , Adulto , Sequência de Bases , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Proteínas da Mielina/genética , Linhagem , Adulto Jovem , Proteína beta-1 de Junções Comunicantes
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