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  • Identification of S-nitrosylated proteins in injury-induced neurogenesis
    Publication . Lourenço, Ana Sofia Maximiano Leitão Ribeiro; Araújo, Inês
    In the adult mammalian brain, new neurons can be generated (adult neurogenesis) due to the presence of neural stem cells (NSC). Adult neurogenesis can be affected by several factors and is particularly altered in pathological conditions, which can increase NSC proliferation, migration and differentiation into neurons. However, neurogenesis after brain injury is not efficient due to low survival of new neurons. Brain insults trigger neuroinflammation with activation of microglia, which release several molecules, such as nitric oxide (NO). NO from inflammatory origin enhances adult neurogenesis through ERK/MAPK pathway signaling, but the exact mechanism is unknown. NO can directly modify protein function through S-nitrosylation, the addition of S-nitrosothiol to a cysteine thiol group. In this work, we aimed to validate new putative targets of S-nitrosylation by NO in NSC that are involved in the ERK/MAPK pathway, which were recently identified by our group. Here, we describe the S-nitrosylation of these new targets in conditions of increased post-injury neurogenesis mediated by NO and study in more detail phosphatidylethanolamine binding protein 1 (PEBP-1). PEBP-1 inhibits the ERK/MAPK pathway by binding to c-Raf and is the most promising target for neurogenesis. We show that S-nitrosylation of cysteine 133 of PEBP-1 is necessary for ERK phosphorylation induced by NO in NSC, which can be a mechanism involved in the release of PEBP-1 inhibitory function in the ERK/MAPK pathway. Moreover, in a model of post-injury neurogenesis we show that 14-3-3, 14-3-3 , hnRNP K and PEBP-1 are transiently S-nitrosylated following seizures, according to their role in the ERK/MAPK pathway, preceding the onset of proliferation of NSC. Overall, our data shows that these proteins may be important for regulation of post-injury neurogenesis and suggests that they could be good candidates for regulation, in order to enhance NSC proliferation and neuronal replacement efficiency following brain injury.
    2018-06-28Doctoral thesis Open Access Show more