RESUMO
Alterations in the functions of neuronal RNA-binding proteins (RBPs) can contribute to neurodegenerative diseases. However, neurons also express a set of widely distributed RBPs that may have developed specialized functions. Here, we show that the ubiquitous member of the otherwise neuronal Elavl/Hu family of RNA-binding proteins, Elavl1/HuR, has a neuroprotective role. Mice engineered to lack exclusively HuR in the hippocampal neurons of the central nervous system (CNS), maintain physiologic levels of neuronal Elavls and develop a partially diminished seizure response following strong glutamatergic excitation; however, they display an exacerbated neurodegenerative response subsequent to the initial excitotoxic event. This response was phenocopied in hippocampal cells devoid of ionotropic glutamate receptors in which the loss of HuR results in enhanced mitochondrial dysfunction, oxidative damage and programmed necrosis solely after glutamate challenge. The molecular dissection of HuR and nElavl mRNA targets revealed the existence of a HuR-restricted posttranscriptional regulon that failed in HuR-deficient neurons and is involved in cellular energetics and oxidation defense. Thus, HuR acts as a specialized controller of oxidative metabolism in neurons to confer protection from neurodegeneration.
Assuntos
Proteína Semelhante a ELAV 1/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/metabolismo , Convulsões/metabolismo , Animais , Proteína Semelhante a ELAV 1/genética , Ácido Glutâmico/genética , Hipocampo/patologia , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Oxirredução , Estresse Oxidativo/genética , Convulsões/genética , Convulsões/patologiaRESUMO
Progress towards amelioration and eventual cure of human cognitive disorders requires understanding the molecular signaling mechanisms that normally govern learning and memory. The fly Drosophila melanogaster has been instrumental in the identification of molecules and signaling pathways essential for learning and memory, because genetic screens have produced mutants in these processes and the system facilitates integrated genetic, molecular, histological and behavioral analyses. We discuss the behavioral paradigms available to assess associative learning and memory in the fly, the contributions learning and memory mutants have made to our understanding of the molecular mechanisms that govern learning and memory, and predictions stemming from the nature of the affected genes. Furthermore, we consider the multiple well-established behavioral assays available and the powerful molecular genetics of the fly with regard to development of models of human cognitive disorders and their pharmacological treatment.