RESUMEN
Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal late-onset neurodegenerative disease. Familial cases of ALS (FALS) constitute approximately 10% of all ALS cases, and mutant superoxide dismutase 1 (SOD1) is found in 15-20% of FALS. SOD1 mutations confer a toxic gain of unknown function to the protein that specifically targets the motor neurons in the cortex and the spinal cord. We have previously shown that the autosomal dominant Legs at odd angles (Loa) mutation in cytoplasmic dynein heavy chain (Dync1h1) delays disease onset and extends the life span of transgenic mice harboring human mutant SOD1(G93A). In this study we provide evidence that despite the lack of direct interactions between mutant SOD1 and either mutant or wild-type cytoplasmic dynein, the Loa mutation confers significant reductions in the amount of mutant SOD1 protein in the mitochondrial matrix. Moreover, we show that the Loa mutation ameliorates defects in mitochondrial respiration and membrane potential observed in SOD1(G93A) motor neuron mitochondria. These data suggest that the Loa mutation reduces the vulnerability of mitochondria to the toxic effects of mutant SOD1, leading to improved mitochondrial function in SOD1(G93A) motor neurons.
Asunto(s)
Modelos Animales de Enfermedad , Dineínas/genética , Mitocondrias/metabolismo , Enfermedad de la Neurona Motora/metabolismo , Mutación , Superóxido Dismutasa/genética , Animales , Citoplasma/metabolismo , Femenino , Heterocigoto , Potenciales de la Membrana , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas Motoras/metabolismo , Superóxido Dismutasa-1RESUMEN
The Flamingo gene encodes a seven-pass transmembrane receptor of the cadherin super family and is one of a growing number of components identified as being necessary for the establishment of planar polarity in the Drosophila wing. Although vertebrate homologues of Flamingo have been identified in both man and mice, no function has as yet been ascribed to them. Here, we report the cloning of the Xenopus homologue of Flamingo (XFmi). XFmi is expressed in the dorsal ectoderm during gastrulation and in the forebrain and midbrain subsequently. We show that ectopic expression of the murine Flamingo gene can prevent the wnt mediated posteriorisation of the neural plate by interfering with the canonical wnt signalling pathway.
Asunto(s)
Cadherinas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Xenopus laevis/embriología , Xenopus laevis/fisiología , Proteínas de Pez Cebra , Animales , Tipificación del Cuerpo/genética , Tipificación del Cuerpo/fisiología , Cadherinas/genética , Proteínas del Citoesqueleto/fisiología , Drosophila/genética , Drosophila/crecimiento & desarrollo , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiología , Regulación del Desarrollo de la Expresión Génica , Genes Homeobox , Humanos , Ratones , Modelos Biológicos , Sistema Nervioso/embriología , Proteínas Proto-Oncogénicas/genética , Transducción de Señal , Transactivadores/fisiología , Proteínas Wnt , Proteínas de Xenopus , Xenopus laevis/genética , beta CateninaRESUMEN
Several recent studies have highlighted the role of axonal transport in the pathogenesis of motor neuron diseases. Mutations in genes that control microtubule regulation and dynamics have been shown to cause motor neuron degeneration in mice and in a form of human motor neuron disease. In addition, mutations in the molecular motors dynein and kinesins and several proteins associated with the membranes of intracellular vesicles that undergo transport cause motor neuron degeneration in humans and mice. Paradoxically, evidence from studies on the legs at odd angles (Loa) mouse and a transgenic mouse model for human motor neuron disease suggest that partial limitation of the function of dynein may in fact lead to improved axonal transport in the transgenic mouse, leading to delayed disease onset and increased life span.