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Höglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, PSP Genetics Study Group, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Müller U, Schellenberg GD. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet. 2011 Jun 19;43(7):699-705. PubMed.
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VU University Medical Center
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:
Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W. The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. Am J Pathol. 2009 Apr;174(4):1241-51. PubMed.
Nijholt DA, de Graaf TR, van Haastert ES, Oliveira AO, Berkers CR, Zwart R, Ovaa H, Baas F, Hoozemans JJ, Scheper W. Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer's disease. Cell Death Differ. 2011 Jun;18(6):1071-81. PubMed.
Scheper W, Hoozemans JJ. Endoplasmic reticulum protein quality control in neurodegenerative disease: the good, the bad and the therapy. Curr Med Chem. 2009;16(5):615-26. PubMed.
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