RESUMO
Mitochondrial dysfunction originating from mutations in Complex I genes may play a role in the pathogenesis of Parkinson's disease (PD). In this study, the entire ND1 coding sequence was sequenced in 84 newly diagnosed PD cases and 127 age/gender-matched controls. Numerous missense mutations were found at low frequency (<5%), whereas a thymidine to cytosine missense mutation at position 4216 that results in the replacement of tyrosine with histidine was found in 25% of the PD case samples and in 18% of the controls. When calculated according to gender, the 4216 mutation was observed in 26% of the male cases versus 16% of male controls (Odds Ratio [OR] = 1.85; 95% CI = 0.79-4.34). In contrast, females exhibited approximately equal frequencies among cases (22.5%) and controls (21%), yielding an OR of 1.08 (95% C.I. = 0.36-3.22). The findings indicate only a weak association of this genetic variant with PD.
Assuntos
Proteínas de Insetos/genética , Mitocôndrias/metabolismo , Mutação/genética , NADH Desidrogenase , Doença de Parkinson/genética , Humanos , Proteínas de Insetos/análise , Linfócitos/química , Mutação de Sentido Incorreto/genética , Polimorfismo Genético/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNARESUMO
The search for genetic polymorphisms relevant to Parkinson's disease etiology and pathogenesis has been motivated by recent thinking emphasizing the potential significance of gene-environment interactions. Especially influential to this research have been the MPTP model of PD induction, hypotheses concerning oxidative stressor reactions, and epidemiological observations of an inverse relation between cigarette smoking and PD risk. This brief review summarizes trends in genetic polymorphism research, with examples provided by investigations of cytochrome P450 enzymes, monoamine oxidase, superoxide dismutase, and mitochondrial genes.
Assuntos
Doença de Parkinson/genética , Polimorfismo Genético/genética , Animais , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , DNA Mitocondrial/genética , Humanos , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Doença de Parkinson/enzimologia , Polimorfismo Genético/fisiologia , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
Methylmercury (MeHg) is recognized as a significant environmental hazard, particularly to the development of the nervous system. Studies on the mechanism of MeHg-induced toxicity reveal that inhibition of cell cycle progression may be one way by which MeHg interferes with normal development. In this study, we utilized primary rodent embryonic neuronal cell (CNS) and limb bud (LB) cultures to determine the mRNA expression level of two genes involved in cell cycle arrest, Gadd45 and Gadd153, both during cellular differentiation and in response to MeHg exposure. A differential expression pattern of Gadd45 and Gadd153 was observed during CNS and LB differentiation in culture. However, both CNS and LB cells responded to MeHg exposure with a concentration-dependent increase in Gadd45 and Gadd153 mRNA. Previous studies have shown that MeHg exposure (2 microm) of CNS cells for 24 hr causes a fourfold decrease in the number of cells passing through the cell cycle. The present study shows that at the same exposure concentration, a five- to eightfold increase in Gadd45 mRNA levels and a two- to fourfold increase of Gadd153 was observed. Induction of Gadd45 was also noted in adult female mice chronically exposed to 10 ppm MeHg, a dose that caused developmental toxicity in vivo. Based on the known involvement of the Gadd genes in cell cycle arrest, activation of these genes could be one mechanism by which MeHg interferes with the cell cycle in adult and developing organisms.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Dano ao DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Compostos de Metilmercúrio/toxicidade , Animais , Northern Blotting , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Diferenciação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Sistema Nervoso Central/embriologia , Relação Dose-Resposta a Droga , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismoRESUMO
The effects of a highly cytokinin-active urea derivative, N-phenyl-N'-1,2,3-thiadiazol-5-ylurea (Thidiazuron), and zeatin on cytokinin-autonomous growth and the metabolism of N(6)-(Delta(2)-isopentenyl)[8-(14)C]adenosine ([(14)C]i(6) Ado) were examined in callus tissues of two Phaseolus lunatus genotypes, cv Jackson Wonder and P.I. 260415. Tissues of cv Jackson Wonder maintained on any concentration of Thidiazuron became cytokinin autonomous, whereas only tissues exposed to suboptimal concentrations of zeatin displayed cytokinin-autonomous growth. Tissues of P.I. 260415 remained cytokinin dependent under all these conditions. The metabolism of [(14)C]i(6) Ado was similar for the two genotypes, but differed with the medium used. [(14)C]i(6) Ado was rapidly converted to N(6)-(Delta(2)-isopentenyl)[8-(14)C]adenosine 5'-P ([(14)C]i(6) AMP) by tissues grown on zeatin-containing medium, whereas only traces of the nucleotide were formed in tissues grown on medium with Thidiazuron. Incubation with [(14)C] i(6) AMP of tissues grown in the presence of Thidiazuron resulted in rapid conversion to [(14)C]i(6) Ado, while [(14)C]i(6) AMP persisted in tissues maintained on zeatin. Thus, Thidiazuron appears to stimulate enzyme activity converting the ribonucleotide to ribonucleoside. Although the cytokininactive phenylureas and adenine derivatives differ in their effects on cytokinin autonomy as well as nucleotide formation, the two types of effects do not seem to be related.
