RESUMO
Excitotoxic neuronal damage caused by overactivation of N-methyl-D-aspartate glutamate receptors (NMDARs) is thought to be a principal cause of neuronal loss after stroke and brain trauma. Here we report that activation of sterol regulatory element binding protein-1 (SREBP-1) transcription factor in affected neurons is an essential step in NMDAR-mediated excitotoxic neuronal death in both in vitro and in vivo models of stroke. The NMDAR-mediated activation of SREBP-1 is a result of increased insulin-induced gene-1 (Insig-1) degradation, which can be inhibited with an Insig-1-derived interference peptide (Indip) that we have developed. Using a focal ischemia model of stroke, we show that systemic administration of Indip not only prevents SREBP-1 activation but also substantially reduces neuronal damage and improves behavioral outcome. Our study suggests that agents that reduce SREBP-1 activation such as Indip may represent a new class of neuroprotective therapeutics against stroke.
Assuntos
Isquemia Encefálica/fisiopatologia , Córtex Cerebral/irrigação sanguínea , Receptores de N-Metil-D-Aspartato/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Animais , Linhagem Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
Critical times of involvement of areas important to working memory were examined both with pitch and audioverbal N-back tasks using single-pulse transcranial magnetic stimulation (TMS). TMS was administered to 12 healthy participants over dorsolateral prefrontal and inferior parietal regions in each hemisphere at four different times after stimulus onset (250, 450, 650, and 850 ms). For the pitch N-back task, interference with working memory, as evidenced by a significant increase in reaction time, was observed with TMS over the right hemisphere regions. In contrast, for the audioverbal N-back task, TMS resulted in significantly increased reaction time only for left inferior parietal TMS delivered 450 ms after stimulus onset. These results imply different hemispheric specializations for pitch and audioverbal working memory.
Assuntos
Mapeamento Encefálico , Córtex Cerebral/fisiologia , Dominância Cerebral/fisiologia , Memória de Curto Prazo/fisiologia , Percepção da Altura Sonora/fisiologia , Aprendizagem Verbal/fisiologia , Estimulação Acústica/métodos , Adulto , Análise de Variância , Relação Dose-Resposta à Radiação , Estimulação Elétrica , Eletromiografia/métodos , Feminino , Humanos , Masculino , Tempo de Reação/fisiologia , Estimulação Magnética TranscranianaRESUMO
The B30.2/SPRY domain is present in approximately 700 eukaryotic (approximately 150 human) proteins, including medically important proteins such as TRIM5alpha and Pyrin. Nonetheless, the functional role of this modular domain remained unclear. Here, we report the crystal structure of an SPRY-SOCS box family protein GUSTAVUS in complex with Elongins B and C, revealing a highly distorted two-layered beta-sandwich core structure of its B30.2/SPRY domain. Ensuing studies identified one end of the beta-sandwich as the surface interacting with an RNA helicase VASA with a 40 nM dissociation constant. The sequence variation in TRIM5alpha responsible for HIV-1 restriction and most of the mutations in Pyrin causing familial Mediterranean fever map on this surface, implicating the corresponding region in many B30.2/SPRY domains as the ligand-binding site. The amino acids lining the binding surface are highly variable among the B30.2/SPRY domains, suggesting that these domains are protein-interacting modules, which recognize a specific individual partner protein rather than a consensus sequence motif.
