RESUMO
How pseudouridylation (Ψ), the most common and evolutionarily conserved modification of rRNA, regulates ribosome activity is poorly understood. Medically, Ψ is important because the rRNA Ψ synthase, DKC1, is mutated in X-linked dyskeratosis congenita (X-DC) and Hoyeraal-Hreidarsson (HH) syndrome. Here, we characterize ribosomes isolated from a yeast strain in which Cbf5p, the yeast homolog of DKC1, is catalytically impaired through a D95A mutation (cbf5-D95A). Ribosomes from cbf5-D95A cells display decreased affinities for tRNA binding to the A and P sites as well as the cricket paralysis virus internal ribosome entry site (IRES), which interacts with both the P and the E sites of the ribosome. This biochemical impairment in ribosome activity manifests as decreased translational fidelity and IRES-dependent translational initiation, which are also evident in mouse and human cells deficient for DKC1 activity. These findings uncover specific roles for Ψ modification in ribosome-ligand interactions that are conserved in yeast, mouse, and humans.
Assuntos
Proteínas de Ciclo Celular/deficiência , Disceratose Congênita/genética , Retardo do Crescimento Fetal/genética , Hidroliases/deficiência , Hidroliases/metabolismo , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Nucleares/deficiência , RNA Ribossômico/metabolismo , RNA de Transferência/metabolismo , Ribonucleoproteínas Nucleares Pequenas/deficiência , Saccharomyces cerevisiae/genética , Animais , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Disceratose Congênita/enzimologia , Retardo do Crescimento Fetal/enzimologia , Genes Reporter , Humanos , Hidroliases/genética , Deficiência Intelectual/enzimologia , Luciferases/análise , Camundongos , Microcefalia/enzimologia , Proteínas Associadas aos Microtúbulos/genética , Mutação , Proteínas Nucleares/genética , Plasmídeos , Biossíntese de Proteínas , RNA Ribossômico/química , RNA Ribossômico/genética , RNA de Transferência/química , RNA de Transferência/genética , Ribonucleoproteínas Nucleares Pequenas/genética , Ribossomos/química , Ribossomos/metabolismo , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência de Aminoácidos , Transdução GenéticaRESUMO
OBJECTIVES: To evaluate deficits of delayed free recall in euthymic older patients with bipolar disorder and relate deficits to resting cerebral metabolism. DESIGN: Two group, between subjects. SETTING: Outpatient. PARTICIPANTS: Participants included 16 older adult (mean age, 58.7 years; SD = 7.5) euthymic outpatients with bipolar disorder (10 Type I and 6 Type II) and 11 healthy comparison subjects (mean age, 58.3 years; SD = 5.2). MEASUREMENTS: All participants received resting positron emission tomography with (18)flurodeoxyglucose and, within 10 days, delayed free verbal recall testing with the California Verbal Learning Test II. RESULTS: Patients with bipolar disorder, relative to healthy comparison subjects, had significantly poorer delayed free verbal recall. In patients with bipolar disorder, relative to healthy comparison subjects, prefrontal hypometabolism (dorsolateral prefrontal cortex) and paralimbic hypermetabolism (hippocampus, parahippocampal gyrus, and superior temporal gyrus) was associated with recall deficits in patients with bipolar disorder. Prefrontal and limbic metabolism were inversely related. CONCLUSION: Our findings demonstrate an association between prefrontal hypometabolism and paralimbic hypermetabolism and verbal memory deficits in euthymic older patients with bipolar disorder. Verbal memory deficits may be a clinical consequence of corticolimbic dysregulation in bipolar disorder, even during euthymia. This suggests that such dysregulation and related deficits could be bipolar disorder traits.
Assuntos
Transtorno Bipolar/metabolismo , Encefalopatias Metabólicas/metabolismo , Sistema Límbico/metabolismo , Rememoração Mental , Córtex Pré-Frontal/metabolismo , Descanso , Aprendizagem Verbal , Envelhecimento , Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias Metabólicas/diagnóstico por imagem , Feminino , Fluordesoxiglucose F18 , Humanos , Processamento de Imagem Assistida por Computador/métodos , Sistema Límbico/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos/estatística & dados numéricos , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
Metabolic syndrome is prevalent in older adults and increases the risk of cardiovascular disease. Second-generation antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone) increase the risk of metabolic syndrome and present many challenges for psychiatrists. In this article, we review the relationships between second-generation antipsychotics and metabolic syndrome with a focus on older adults. Because few studies focus exclusively on older adults, we augment this review with relevant findings from younger adults. The differential risk factors of each medication are reviewed, as are recent findings in monitoring and treating metabolic syndrome. Olanzapine and clozapine are more strongly associated with metabolic risks, whereas aripiprazole and ziprasidone are less associated. Although lifestyle modifications can help to reduce some aspects of metabolic syndrome, lifestyle modifications in conjunction with metformin therapy appear to be most effective.
Assuntos
Transtornos Psicóticos Afetivos/tratamento farmacológico , Antipsicóticos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Síndrome Metabólica/induzido quimicamente , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos Afetivos/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Antipsicóticos/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Terapia Combinada , Estudos Transversais , Feminino , Humanos , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/prevenção & controle , Metformina/uso terapêutico , Transtornos Psicóticos/epidemiologia , Fatores de Risco , Aumento de Peso/efeitos dos fármacosRESUMO
Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1(m)). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1(S485G)) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1(S485G) mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27.