The aging brain, a key target for the future: The protein kinase C involvement

The brain represents the primary centre for the regulation and control of all our body activities, receiving and interpreting sensory impulses and transmitting information to the periphery. Most importantly, it is also the seat of consciousness, thought, emotion and especially memory, being in fact able to encode, store and recall any information. Memory is really what makes possible so many of our complex cognitive functions, including communication and learning, and surely without memory, life would lose all of its glamour and purpose. Age-associated mental impairment can range in severity from forgetfulness at the border with pathology to dementia, such as in Alzheimer's disease. In recent years, one of the most relevant observations of research on brain aging relates to data indicating that age-related cognitive decline is not only due to neuronal loss, as previously thought; instead, scientists now believe that age-associated functional changes have more to do with the dysfunctions occurring over time. Within this context a prominent role is certainly played by signal transduction cascades which guarantee neuronal cell to elaborate coordinated responses to the multiple signals coming from the outside and to adapt itself to the environmental changes and requests. This review will focus the attention on protein kinase C pathway, with a particular interest on its activation process, and on the role of protein-lipid and protein-protein interactions to selectively localize the cellular responses. Furthermore, information is emerging and will be discussed on the possibility of mRNA stabilization through PKC activation. This review will also approach the issue on how alterations of these molecular cascades may have implications in physiological and pathological brain aging, such as Alzheimer's disease.     

Dynamic association with polysomes during P19 neuronal differentiation and an untranslated-region-dependent translation regulation of the tau mRNA by the tau mRNA-associated proteins IMP1, HuD, and G3BP1

Regulation of mRNA translation is a key step in mediating neuronal polarity during differentiation, insofar as neuronal polarity is partially determined by local translation of specific mRNA molecules as dendrites and axons are emanating. The multiplicity of mRNA-binding proteins in neurons plays an essential role in controlling mRNA translation. These proteins are associated with ribosomes and translation factors, thereby regulating both temporally and spatially the translation process. In a previous study, we have shown an association among the tau mRNA-binding proteins HuD, IMP1, and G3BP1 with translating polysomes in P19 neurons. In the present study, we determined the dynamics of the association among G3BP1, IMP1, and HuD with polysomes through P19 neuronal differentiation as well as the functional effect of these proteins on tau mRNA translation. We show a novel, differentiation-dependent association of these proteins with polysomes. In addition, we show a strong, negative effect on translation of the tau mRNA by IMP1, G3BP1, and HuD proteins in HEK-293 cells. To our knowledge this is the first observation of a direct translational role of G3BP1 for any mRNA and the first report of a translation inhibition by IMP1 and HuD on the tau mRNA in a cell system. The translation inhibition is shown to be mediated by the tau mRNA 3'untranslated regions (UTRs), thus giving a new, translational role for these sequences, which were previously implicated in mRNA stabilization. We also define a novel mechanism for IMP1 binding to tau mRNA, which suggests a conformational binding, which is not sequence dependent.