Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibition
|Author/s||Gavilán Dorronzoro, María de la Paz
Pintado Losa, Cristina
Gavilán Dorronzoro, Elena
Jiménez Muñoz, Sebastián
Ríos Sánchez, Rosa María
Vitorica Ferrández, Francisco Javier
Castaño Navarro, Angélica
Ruano Caballero, Diego
|Department||Universidad de Sevilla. Departamento de Bioquímica y Biología Molecular|
|Abstract||Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age-related neurodegenerative disorders. However, the mechanisms linking proteasome ...
Dysfunctions of the ubiquitin proteasome system (UPS) have been proposed to be involved in the aetiology and/or progression of several age-related neurodegenerative disorders. However, the mechanisms linking proteasome dysfunction to cell degeneration are poorly understood. We examined in young and aged rat hippocampus the activation of the unfolded protein response (UPR) under cellular stress induced by proteasome inhibition. Lactacystin injection blocked proteasome activity in young and aged animals in a similar extent and increased the amount of ubiquitinated proteins. Young animals activated the three UPR arms, IRE1α, ATF6α and PERK, whereas aged rats failed to induce the IRE1α and ATF6α pathways. In consequence, aged animals did not induce the expression of pro-survival factors (chaperones, Bcl-XL and Bcl-2), displayed a more sustained expression of proapoptotic markers (CHOP, Bax, Bak and JKN), an increased caspase-3 processing. At the cellular level, proteasome inhibition induced neuronal damage in young and aged animals as assayed using Fluorojade-B staining. However, degenerating neurons were evident as soon as 24 h postinjection in aged rats, but it was delayed up to 3 days in young animals. Our findings show evidence supporting age-related dysfunctions in the UPR activation as a potential mechanism linking protein accumulation to cell degeneration. An imbalance between pro-survival and pro-apoptotic proteins, because of noncanonical activation of the UPR in aged rats, would increase the susceptibility to cell degeneration. These findings add a new molecular vision that might be relevant in the aetiology of several age-related neurodegenerative disorders.
|Citation||Gavilán Dorronzoro, M.P., Pintado Losa, C., Gavilán Dorronzoro, E., Jiménez Muñoz, S., Ríos Sánchez, R.M., Vitorica Ferrández, F.J.,...,Ruano Caballero, D. (2009). Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibition. Aging Cell, 8 (6), 654-665.|