RESUMEN
p150(Glued) is the major subunit of dynactin, a complex that functions with dynein in minus-end-directed microtubule transport. Mutations within the p150(Glued) CAP-Gly microtubule-binding domain cause neurodegenerative diseases through an unclear mechanism. A p150(Glued) motor neuron degenerative disease-associated mutation introduced into the Drosophila Glued locus generates a partial loss-of-function allele (Gl(G38S)) with impaired neurotransmitter release and adult-onset locomotor dysfunction. Disruption of the p150(Glued) CAP-Gly domain in neurons causes a specific disruption of vesicle trafficking at terminal boutons (TBs), the distal-most ends of synapses. Gl(G38S) larvae accumulate endosomes along with dynein and kinesin motor proteins within swollen TBs, and genetic analyses show that kinesin and p150(Glued) function cooperatively at TBs to coordinate transport. Therefore, the p150(Glued) CAP-Gly domain regulates dynein-mediated retrograde transport at synaptic termini, and this function of dynactin is disrupted by a mutation that causes motor neuron disease.
Asunto(s)
Proteínas Asociadas a Microtúbulos/metabolismo , Mutación/genética , Terminales Presinápticos/fisiología , Animales , Animales Modificados Genéticamente , Drosophila , Proteínas de Drosophila/genética , Complejo Dinactina , Electrofisiología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Cinesinas/genética , Cinesinas/metabolismo , Larva , Potenciales de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Modelos Biológicos , Enfermedad de la Neurona Motora/genética , Neuronas Motoras/fisiología , Unión Neuromuscular/genética , Unión Neuromuscular/fisiología , Fotoblanqueo , Unión Proteica/genética , Dominios y Motivos de Interacción de Proteínas/genética , Transporte de Proteínas/genética , Transmisión Sináptica/genéticaRESUMEN
BACKGROUND: Silicosis is the second commonest notified occupational disease in Hong Kong. AIM: To characterize the determinants of spirometric abnormalities in silicosis. METHOD: The spirometric patterns of consecutive silicotic patients on confirmation by the Pneumoconiosis Medical Board from 1991 to 2002 were correlated with demographic characteristics, occupational history, smoking history, tuberculosis (TB) history and radiographic features by univariate and multiple regression analyses. RESULTS: Of 1576 silicotic patients included, 55.6% showed normal spirometry, 28.5% normal forced vital capacity (FVC>or=80% predicted) but reduced forced expiratory ratio (FER<70%), 7.6% reduced FVC but normal FER, and 8.4% reduced both FVC and FER. Age, ever-smoking, cigarette pack-years, industry, job type, history of TB, size of lung nodules and progressive massive fibrosis (PMF) were all significantly associated with airflow limitation on univariate analysis (all P<0.05), while sex and profusion of nodules were not. Only age, cigarette pack-years, history of TB, size of lung nodules and PMF remained as significant independent predictors of airflow obstruction in multiple logistic regression analysis. After controlling for airflow obstruction, only shorter exposure duration, history of TB and profusion of nodules were significant independent predictors of reduced FVC. As well as age, history of TB, cigarette pack-years, PMF and nodule size contributed comparable effects to airflow obstruction in multiple linear regression analyses, while profusion of nodules was the strongest factor for reduced vital capacity. CONCLUSIONS: In an occupational compensation setting, disease indices and history of tuberculosis are independent predictors of both airflow obstruction and reduced vital capacity for silicotic patients.