Activation of the unfolded protein response and granulovacuolar degeneration are not common features of human prion pathology.

Vera I Wiersma,Wim Van Hecke,Wiep Scheper,Annemieke J M Rozemuller,Martijn A J Van Osch,Jeroen J M Hoozemans,Will J M Hermsen

doi:10.1186/s40478-016-0383-7

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0383-7) contains supplementary material, which is available to authorized users.

Highlights

Human prion diseases are rare, rapidly progressive, invariably lethal neurodegenerative diseases, symptomatically characterized by severe memory impairment and a general decline in cognitive functions, which may include motor, linguistic, executive and social skills [1]
It has earlier been shown that the unfolded protein response (UPR) activation marker phosphorylated PERK (pPERK) can only be detected in human prion disease cases with concomitant Alzheimer’s disease (AD) pathology [28]
In the present study we controlled for the presence of concomitant AD pathology in the frontal cortex of human prion disease cases using the Braak staging for neurofibrillary tangles, which was applied to almost all prion disease cases included in this study (Table 1)

Summary

Introduction

Human prion diseases are rare, rapidly progressive, invariably lethal neurodegenerative diseases, symptomatically characterized by severe memory impairment and a general decline in cognitive functions, which may include motor, linguistic, executive and social skills [1]. PrPSc arises after the post-translational conformational conversion of the cellular prion protein (PrPC). During human prion diseases PrPC is converted into insoluble, β-sheet rich PrPSc aggregates that are usually resistant to digestion by proteinase-K. This pathological PrPSc conformer exhibits intriguing characteristics that, once formed, ensure conversion of native PrPC into PrPSc and propagation of pathology to neighbouring cells [6,7,8,9,10]

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