RESUMEN
Zellweger syndrome (ZS) is a peroxisome biogenesis disorder that involves significant neuropathology, the molecular basis of which is still poorly understood. Using a mouse model of ZS with brain-restricted deficiency of the peroxisome biogenesis protein PEX13, we demonstrated an expanded and morphologically modified brain mitochondrial population. Cultured fibroblasts from PEX13-deficient mouse embryo displayed similar changes, as well as increased levels of mitochondrial superoxide and membrane depolarization; this phenotype was rescued by antioxidant treatment. Significant oxidative damage to neurons in brain was indicated by products of lipid and DNA oxidation. Similar overall changes were observed for glial cells. In toto, these findings suggest that mitochondrial oxidative stress and aberrant mitochondrial dynamics are associated with the neuropathology arising from PEX13 deficiency.
Asunto(s)
Encéfalo/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo/fisiología , Síndrome de Zellweger/metabolismo , Animales , Western Blotting , Encéfalo/patología , Células Cultivadas , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fibroblastos/patología , Técnica del Anticuerpo Fluorescente , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Mitocondrias/patología , Neuroglía/metabolismo , Neuroglía/patología , Superóxido Dismutasa/metabolismo , Triptófano Hidroxilasa/metabolismo , Síndrome de Zellweger/patologíaRESUMEN
In all multicellular animals, successful embryogenesis is dependent on the ability of cells to detect the status of the local environment and respond appropriately. The nature of the extracellular environment is communicated to the intracellular compartment by ligand/receptor interactions at the cell surface. The Wnt canonical and non-canonical signalling pathways are found in the most primitive metazoans, and they play an essential role in the most fundamental developmental processes in all multicellular organisms. Vertebrates have expanded the number of Wnts and Frizzled receptors and have additionally evolved novel Wnt receptor families (Ryk, Ror). The multiplicity of potential interactions between Wnts, their receptors and downstream effectors has exponentially increased the complexity of the signal transduction network. Signalling through each of the Wnt pathways, as well as crosstalk between them, plays a critical role in the establishment of the complex architecture of the vertebrate central nervous system. In this review, we explore the signalling networks triggered by non-canonical Wnt/receptor interactions, focussing on the emerging roles of the non-conventional Wnt receptors Ryk and Ror. We describe the role of these pathways in neural tube formation and axon guidance where Wnt signalling controls tissue polarity, coordinated cell migration and axon guidance via remodelling of the cytoskeleton.