This tremendous collaborative effort has yielded very exciting results that will have great impact on tauopathy research. Here we want to highlight the association of risk for PSP with SNPs in the EIF2AK3 region, which encodes the endoplasmic reticulum (ER) stress transducer PERK. ER stress induces the unfolded protein response (UPR), of which PERK is a major component.

Our lab previously reported activation of PERK in AD brain in close correlation with tau pathology (1). Because PERK activation is found in neurons with diffusely distributed phosphorylated tau and not in tangle-bearing neurons, we hypothesized that the activation of the UPR is a very early event in AD pathogenesis that may precede tau pathology.

PSP is a primary tauopathy that has no common co-pathology like the Aβ pathology in AD. The association of EIF2AK3 and risk for this tauopathy points to a key role for the UPR in the development of tau pathology in general, and warrants further investigation of UPR activation in other tauopathies. The UPR is initiated to restore protein homeostasis caused by ER...  Read more

This tremendous collaborative effort has yielded very exciting results that will have great impact on tauopathy research. Here we want to highlight the association of risk for PSP with SNPs in the EIF2AK3 region, which encodes the endoplasmic reticulum (ER) stress transducer PERK. ER stress induces the unfolded protein response (UPR), of which PERK is a major component.

Our lab previously reported activation of PERK in AD brain in close correlation with tau pathology (1). Because PERK activation is found in neurons with diffusely distributed phosphorylated tau and not in tangle-bearing neurons, we hypothesized that the activation of the UPR is a very early event in AD pathogenesis that may precede tau pathology.

PSP is a primary tauopathy that has no common co-pathology like the Aβ pathology in AD. The association of EIF2AK3 and risk for this tauopathy points to a key role for the UPR in the development of tau pathology in general, and warrants further investigation of UPR activation in other tauopathies. The UPR is initiated to restore protein homeostasis caused by ER stress, for example, by activating autophagy (2). What the trigger for UPR activation is and how this affects tau pathology are important challenges for future research and may open the possibility of intervention in tau pathology via the UPR (3).

References:
1. JJM Hoozemans, ES van Haastert, DAT Nijholt, AJM Rozemuller, P Eikelenboom and W Scheper (2009) The Unfolded Protein Response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am. J. Pathol. 174(4):1241-51. Abstract

2. DAT Nijholt, TR de Graaf, ES van Haastert, A Osório Oliveira, CR Berkers, R Zwart, H Ovaa, FBaas, JJM Hoozemans and W Scheper (2011) Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells – implications for Alzheimer’s disease. Cell Death Differ. 18 (6):1071-81. Abstract

3. W Scheper and JJM Hoozemans (2009) Endoplasmic Reticulum Protein Quality Control in Neurodegenerative Disease: The Good, the Bad and the Therapy. Curr. Med. Chem. 16(5): 615-26. Abstract

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