The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies

Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
The Journal of Pathology (Impact Factor: 7.43). 04/2012; 226(5):693-702. DOI: 10.1002/path.3969
Source: PubMed


The unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence of phosphorylated tau (p-tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p-tau, AD brains are characterized by extracellular deposits of β amyloid (Aβ). Recent in vitro studies have shown that Aβ can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1α (pIRE1), which are indicative of an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau pathology (FTLD-tau). Increased presence of UPR activation markers pPERK and pIRE1 was observed in neurons and glia in FTLD-tau cases, in contrast to FTLD subtypes negative for tau pathology or in non-neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of MAPT mutation. A strong association between the presence of UPR activation markers and p-tau was observed in the hippocampus of FTLD-tau cases. Double immunohistochemical staining on FTLD-tau cases revealed that UPR activation is predominantly observed in neurons that show diffuse staining of p-tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p-tau, and occurs independently from Aβ deposits. Our findings provide new pathological insight into the close association between p-tau and UPR activation in tauopathies.

Download full-text


Available from: Wiep Scheper,
60 Reads
  • Source
    • "Phosphorylated tau colocalizes with PERK and IRE1 in neurons Hoozemans et al. 2009, Nijholt et al. 2012, Stutzbach et al. 2013 pPERK, peIF2α Amyloid β peptide accumulation trigger ER stress leading to phosphorylation of PERK and eIF2α "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson’s disease is the second most common neurodegenerative disease which affects almost 1% of the population above the age of 60. It is is characterized by loss of dopaminergic neurons in the striatum and substantia nigra, coupled with the formation of intracellular Lewy bodies in degenerating neurons. Recent evidence suggests endoplasmic reticulum stress as a common and prominent occurrence in the progression of Parkinson’s disease pathogenesis in the affected human brain. One of the cellular defense mechanism to combat endoplasmic reticulum stress due to excessive protein accumulation is through activation of the unfolded protein response pathway. In this review we focus on the impact and role of this unfolded protein response as a causative factor of Parkinson’s disease leading to neurodegeneration.
    Acta neurobiologiae experimentalis 04/2015; 75:1-26. · 1.29 Impact Factor
  • Source
    • "The PERK branch of the UPR has been studied extensively in several neurological disorders, including PD, AD, ALS, and prion disease with its activation detected in disease models and in human diseased tissue samples (Colla et al., 2012a,2012b; Cornejo and Hetz, 2013; Holtz and O'Malley, 2003; Hoozemans and Scheper, 2012; Matus et al., 2013; Mutez et al., 2014; Nijholt et al., 2012; Saxena et al., 2009; Wang et al., 2011). Several groups have shown the therapeutic benefit of small molecule inhibition of PERK or inhibition of eiF2α phosphorylation resulting in decreased cytotoxicity in several disease models of the aforementioned neurological disorders (Colla et al., 2012a,2012b; Ma et al., 2013; Moreno et al., 2012, 2013; Silva et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The unfolded protein response (UPR) monitors the folding environment within the endoplasmic reticulum (ER). Accumulation of misfolded proteins within the ER activates the UPR resulting in the execution of adaptive or non-adaptive signaling pathways. α-Synuclein (α-syn) whose accumulation and aggregation define the pathobiology of Parkinson's disease (PD) has been shown to inhibit ER-Golgi transit of COPII vesicles. ATF6, a protective branch of the UPR, is processed via COPII mediated ER-Golgi transit following its activation via ER stress. Using cellular PD models together with biochemical reconstitution assays, we showed that α-syn inhibited processing of ATF6 directly through physical interactions and indirectly through restricted incorporation into COPII vesicles. Impaired ATF6 signaling was accompanied by decreased ER-associated degradation (ERAD) function and increased pro-apoptotic signaling. The mechanism by which α-syn inhibits ATF6 signaling expands our understanding of the role, ER stress, and the UPR play in neurodegenerative diseases such as PD. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Disease 02/2015; 76. DOI:10.1016/j.nbd.2015.02.005 · 5.08 Impact Factor
  • Source
    • "At least two different fields of view were analyzed per patient. Ubiquilin 2 and AT8 signals were unmixed using Nuance spectral imaging system (CRi, Woburn, MA, USA) as described previously [20]. AT8 and ubiquilin 2 double stained sections of 7 AD cases (Table 1) were used to compare ubiquilin 2 signals between AT8 positive and AT8 negative cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulation of aberrant proteins in inclusion bodies is a hallmark of many neurodegenerative diseases. Impairment of proteolytic systems is a common event in these protein misfolding diseases. Recently, mutations in the UBQLN 2 gene encoding ubiquilin 2 have been identified in X-linked amyotrophic lateral sclerosis (ALS). Furthermore, ubiquilin 2 is associated with inclusions in familial and sporadic ALS/dementia, synucleinopathies and polyglutamine diseases. Ubiquilin 2 exerts a regulatory role in proteostasis and thus it has been suggested that ubiquilin 2 pathology may be a common event in neurodegenerative diseases. Tauopathies, a heterogenous group of neurodegenerative diseases accompanied with dementia, are characterized by inclusions of the microtubule-binding protein tau. In the present study, we investigate whether ubiquilin 2 is connected with tau pathology in Alzheimer's disease (AD), supranuclear palsy (PSP) and Pick's disease (PiD) and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We show that ubiquilin 2 positive inclusions are absent in these tauopathies. Furthermore, we find decreased ubiquilin 2 protein levels in AD patients, but our results do not indicate a correlation with tau pathology. Our data show no evidence for involvement of ubiquilin 2 and indicate that other mechanisms underly the proteostatic disturbances in tauopathies.
    PLoS ONE 09/2013; 8(9):e76598. DOI:10.1371/journal.pone.0076598 · 3.23 Impact Factor
Show more