Session Title: Neurodevelopment and Neurodegeneration
ACTIVATION OF THE UNFOLDED PROTEIN RESPONSE FOLLOWING PROTEASOME INHIBITION IS AFFECTED IN AGED RAT HIPPOCAMPUS
M.P. Gavilan1, E. Gavilan2, C. Pintado2, R.M. Rios1, J. Vitorica2, A. Castaño2, D. Ruano2
Dysfunction of the ubiquitin proteasome system (UPS) has been proposed to be involved in the aetiology and/or progression of some age-related neurodegenerative disorders. However, a detailed analysis of the mechanisms underlying cell degeneration due to proteasome dysfunction is currently lacking. Here, we evaluate in young and aged animals, the effect of proteasome inhibition, induced by intra-hippocampal injection of lactacystin, on the endoplasmic reticulum (ER) homeostasis. Our results demonstrate the existence of relevant age-related modifications in the activation of the unfolded protein response (UPR) produced by proteasome inhibition.Young animals fully activated the UPR inducing both pro-survival and pro-apoptotic mediators. By contrast, aged rats did not activate correctly the IRE1 and ATF6 pathways and mostly induced pro-apoptotic factors. Activation of these signalling pathways was also investigated in lactacystin-treated cultured cell lines. In addition, phosphorylation of both Akt and GSK3 proteins increased in young animals subjected to proteasome inhibition whereas it remained unaffected in aged rats. Finally, caspase-3 activation was strongly increased in aged rats but negligible in young animals. These findings provide in vivo evidence supporting that dysfunction in the UPR activation and in the Akt/GSK3 pathway could be a relevant mechanism underlying the neurodegenerative effects of proteasome dysfunction during aging.