title: Activation of the unfolded protein response and granulovacuolar degeneration are not common features of human prion pathology.
abstract: Human prion diseases are fatal neurodegenerative disorders with a genetic, sporadic or infectiously acquired aetiology. Neuropathologically, human prion diseases are characterized by deposition of misfolded prion protein and neuronal loss. In post-mortem brain tissue from patients with other neurodegenerative diseases characterized by protein misfolding, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathology (FTLD-tau), increased activation of the unfolded protein response (UPR) has been observed. The UPR is a cellular stress response that copes with the presence of misfolded proteins. Recent studies have indicated that UPR activation is also involved in experimental models of prion disease and have suggested intervention in the UPR as a therapeutic strategy. On the other hand, it was previously shown that the active form of the UPR stress sensor dsRNA-activated protein kinase-like ER kinase (PERK) is not increased in post-mortem brain tissue samples from human prion disease cases. In the present study, we assessed the active form of another UPR stress sensor, inositol-requiring enzyme 1α (IRE1α), in human post-mortem frontal cortex of a large cohort of sporadic, inherited and acquired prion disease patients (n = 47) and non-neurological controls. Immunoreactivity for phosphorylated IRE1α was not increased in prion disease cases compared with non-neurological controls. In addition, immunoreactivity for phosphorylated PERK was unaltered in human prion disease cases included in the current cohort. Moreover, no difference in the extent of granulovacuolar degeneration, a pathological feature associated with the presence of UPR activation markers, was detected. Our data indicate that, in contrast to AD and primary tauopathies, activation of the UPR is not a common feature of human prion pathology.
authors: Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, P.O. Box 7057 , 1007 MB, Amsterdam, The Netherlands.|Departments of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
authors: Vera I
authors: VI
authors: Wiersma
authors: Dutch Surveillance Centre for Prion Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Wim
authors: W
authors: van Hecke
authors: Department of Clinical Genetics and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands.|Departments of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, The Netherlands.
authors: Wiep
authors: W
authors: Scheper
authors: Dutch Surveillance Centre for Prion Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Martijn A J
authors: MA
authors: van Osch
authors: Dutch Surveillance Centre for Prion Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Will J M
authors: WJ
authors: Hermsen
authors: Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, P.O. Box 7057 , 1007 MB, Amsterdam, The Netherlands.|Dutch Surveillance Centre for Prion Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Annemieke J M
authors: AJ
authors: Rozemuller
authors: Department of Pathology, Amsterdam Neuroscience, VU University Medical Center, P.O. Box 7057 , 1007 MB, Amsterdam, The Netherlands. jjm.hoozemans@vumc.nl.
authors: Jeroen J M
authors: JJ
authors: Hoozemans
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D004722:Endoribonucleases / Q000378:metabolism*; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017096:Prion Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D056811:Unfolded Protein Response; D019892:eIF-2 Kinase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases
keywords: Granulovacuolar degeneration; Inositol-requiring enzyme 1α; Prion disease; Tau; Unfolded protein response; dsRNA-activated protein kinase-like ER kinase