Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells - implications for Alzheimer's disease

Wiep Scheper (1) , Diana A.T. Nijholt (1) , Tjitske R. de Graaf (1) , Rob Zwart (1) , Frank Baas (1) , Elise S van Haastert (1) , Jeroen J.M. Hoozemans (1) , Celia R. Berkers (1) , Huib Ovaa (1) , Ana Osório Oliviera (1)

1 Neurogenetics laboratory

Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore cellular homeostasis via transcriptional and post-transcriptional mechanisms. ER stress is also reported to activate the ER overload response (EOR), which activates transcription via NF-κB. We previously demonstrated that UPR activation is an early event in pre-tangle neurons in Alzheimer's disease (AD) brain. Mis- and unfolded proteins are degraded via the ubiquitin proteasome system (UPS) or autophagy. UPR activation is found in AD neurons displaying both early UPS pathology and autophagic pathology. Here we investigate whether activation of the UPR and/or EOR is employed to enhance the proteolytic capacity of neuronal cells. Expression of the immunoproteasome subunits β2i and β5i is increased in AD brain. However, the expression of the proteasome subunits is not increased by the UPR or EOR. UPR activation does not relocalize the proteasome or increase overall proteasome activity. Therefore proteasomal degradation is not increased by ER stress. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain.

Mots clés: Alzheimer's disease; unfolded protein response; ubiquitin proteasome system; autophagy

Wiep Scheper, Diana A.T. Nijholt, Tjitske R. de Graaf, Rob Zwart, Frank Baas, et al.. Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells - implications for Alzheimer's disease. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2010.176⟩. ⟨hal-00608718⟩