RESUMEN
Gaucher disease is a glycosphingolipid storage disease caused by deficiency of glucocerebrosidase, resulting in the accumulation of glucosylceramide in lysosomes. The neuronopathic forms of this disease are associated with neuronal loss and neurodegeneration. However, the pathophysiological mechanisms leading to prenatal and neonatal death remain uncharacterized. To investigate brain dysfunction in Gaucher disease, we studied the effects of neurotrophic factors during development in a mouse model of Gaucher disease. The expression of brain-derived neurotrophic factor and nerve growth factor was reduced in the cerebral cortex, brainstem, and cerebellum of Gaucher mice, compared with that in wild-type mice. Extracellular signal-regulated kinase (ERK) 1/2 expression was downregulated in neurons from Gaucher mice and correlated with a decreased number of neurons. These results suggest that a reduction in neurotrophic factors could be involved in neuronal loss in Gaucher disease.
Asunto(s)
Ratones , Animales , Transducción de Señal , Neuronas/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Modelos Animales , Ratones Endogámicos C57BL , Sistema de Señalización de MAP Quinasas/fisiología , Enfermedad de Gaucher/metabolismo , Regulación hacia Abajo , Células Cultivadas , Supervivencia Celular , Encéfalo/metabolismoRESUMEN
Gaucher disease, the most common lysosomal storage disorder, is currently treated with enzyme replacement therapy. This approach, however, is ineffective in altering the progression of neurodegeneration in type 2 and type 3 patients due to the difficulty of transferring the recombinant enzyme across the blood-brain barrier. Human immunodeficiency virus type 1 trans-activating transcriptional activator protein (HIV TAT) contains a protein transduction domain that can be added to a fusion protein partner to allow for transport of the partner across membranes. Consequently, we examined the creation, production, and secretion of fusion constructs containing glucocerebrosidase and either wild-type TAT or modified TAT in Sf9 cells. All three constructs exhibited successful expression, with wild-type TAT chimeras showing lower levels of expression than modified TAT chimeras.
Asunto(s)
Humanos , Glucosilceramidasa/biosíntesis , Productos del Gen tat/metabolismo , Células Cultivadas , Enfermedad de Gaucher/metabolismo , Enfermedad de Gaucher/terapia , Glucosilceramidasa/genética , Línea Celular , Membrana Celular/metabolismo , Productos del Gen tat/genética , Transcripción Genética , Transducción Genética , Transporte de Proteínas/genéticaRESUMEN
Os autores analisam a utilizaçäo da reaçäo histoquímica para a fosfatase ácida no fígado e no baço em um paciente portador de doença de Gaucher. E feita uma revisäo dos aspectos fisiopatológicos e dtiopatogênicos da doença e dos meios à disposiçäo do clínico e do patologista para o diagnóstico diferencial entre esta e outras doenças de depósito