RESUMO
Glial reaction is a common feature of neurodegenerative diseases. Recent studies have suggested that reactive astrocytes gain neurotoxic properties, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined. Here, we identify lipocalin 2 (lcn2) as an inducible factor that is secreted by reactive astrocytes and that is selectively toxic to neurons. We show that lcn2 is induced in reactive astrocytes in transgenic rats with neuronal expression of mutant human TAR DNA-binding protein 43 (TDP-43) or RNA-binding protein fused in sarcoma (FUS). Therefore, lcn2 is induced in activated astrocytes in response to neurodegeneration, but its induction is independent of TDP-43 or FUS expression in astrocytes. We found that synthetic lcn2 is cytotoxic to primary neurons in a dose-dependent manner, but is innocuous to astrocytes, microglia, and oligodendrocytes. Lcn2 toxicity is increased in neurons that express a disease gene, such as mutant FUS or TDP-43. Conditioned medium from rat brain slice cultures with neuronal expression of mutant TDP-43 contains abundant lcn2 and is toxic to primary neurons as well as neurons in cultured brain slice from WT rats. Partial depletion of lcn2 by immunoprecipitation reduced conditioned medium-mediated neurotoxicity. Our data indicate that reactive astrocytes secrete lcn2, which is a potent neurotoxic mediator.
Assuntos
Astrócitos/fisiologia , Lipocalinas/metabolismo , Neurônios/patologia , Neurônios/fisiologia , Animais , Animais Geneticamente Modificados , Sequência de Bases , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Meios de Cultivo Condicionados , DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/patologia , Degeneração Lobar Frontotemporal/fisiopatologia , Humanos , Lipocalina-2 , Lipocalinas/genética , Lipocalinas/fisiologia , Lipocalinas/toxicidade , Degeneração Neural/genética , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Neurônios/efeitos dos fármacos , Neurotoxinas/metabolismo , Neurotoxinas/toxicidade , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1RESUMO
The saliva of blood-feeding arthropods contains rich mixtures of ligand binding proteins targeted at inhibiting hemostasis and inflammation in the host. Since blood feeding has evolved many times, different taxonomic groups utilize completely different families of proteins to perform similar tasks. Structural studies performed on a number of these proteins have revealed biologically novel and sophisticated mechanisms used to perform their functions. Here, the results of these structural and mechanistic studies are reviewed.
