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1.
Cell Rep ; 36(10): 109685, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34496257

RESUMO

Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). Here, we assess the impact of stress on the global mRNA localization landscape of human pluripotent stem cell-derived motor neurons (PSC-MNs) using subcellular fractionation with RNA sequencing and proteomics. Transient stress disrupts subcellular RNA and protein distributions, alters the RNA binding profile of SG- and ALS-relevant RBPs and recapitulates disease-associated molecular changes such as aberrant splicing of STMN2. Although neurotypical PSC-MNs re-establish a normal subcellular localization landscape upon recovery from stress, cells harboring ALS-linked mutations are intransigent and display a delayed-onset increase in neuronal cell death. Our results highlight subcellular molecular distributions as predictive features and underscore the utility of cellular stress as a paradigm to study ALS-relevant mechanisms.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Morte Celular/fisiologia , Neurônios Motores/metabolismo , RNA Mensageiro/metabolismo , Esclerose Lateral Amiotrófica/genética , Morte Celular/genética , Grânulos Citoplasmáticos/metabolismo , Grânulos de Ribonucleoproteínas Citoplasmáticas/metabolismo , Grânulos de Ribonucleoproteínas Citoplasmáticas/patologia , Proteínas de Ligação a DNA/metabolismo , Humanos , Mutação/genética , Proteínas de Ligação a RNA/metabolismo
2.
Neuron ; 92(4): 780-795, 2016 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-27773581

RESUMO

HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1. VIDEO ABSTRACT.


Assuntos
Processamento Alternativo/genética , Esclerose Lateral Amiotrófica/genética , Sobrevivência Celular/genética , Fibroblastos/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Neurônios Motores/metabolismo , Transporte Proteico/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Estudos de Casos e Controles , D-Aminoácido Oxidase/genética , D-Aminoácido Oxidase/metabolismo , Imunofluorescência , Expressão Gênica , Perfilação da Expressão Gênica , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas , Camundongos , Mutação , Poliadenilação
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