The unfolded protein response and proteostasis in Alzheimer disease

Amsterdam, The Netherlands.
Autophagy (Impact Factor: 11.42). 08/2011; 7(8):910-1. DOI: 10.4161/auto.7.8.15761
Source: PubMed

ABSTRACT Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore proteostasis in the ER. Previously, we demonstrated that UPR activation is an early event in Alzheimer disease (AD) brain. In our recent work we investigated whether activation of the UPR is employed to enhance the capacity of the ubiquitin proteasome system or autophagy in neuronal cells. We showed that the levels, composition and activity of the proteasome are not regulated by the UPR. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain.

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Available from: Wiep Scheper, Aug 17, 2015
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    • "Under these conditions, ER may be a source of oxidative stress [34]. Several studies established a correlation between abnormal ER function and AD progression [36] [72] and Aβ has been shown to induce ER stress both in vitro and in vivo, subsequently leading to apoptotic cell death [16] [30] [80]. Furthermore, ER dysfunction can partially account for the perturbation of Ca 2+ i homeostasis reported in AD patient's brain and peripheral cells [49]. "
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    ABSTRACT: Oxidative stress and endoplasmic reticulum (ER) stress have been associated with Alzheimer's disease (AD) progression. In this study we analyzed whether oxidative stress involving changes in Nrf2 and ER stress may constitute early events in AD pathogenesis by using human peripheral blood cells and an AD transgenic mouse model at different disease stages. Increased oxidative stress and increased phosphorylated Nrf2 (p(Ser40)Nrf2) were observed in human peripheral blood mononuclear cells (PBMCs) isolated from individuals with mild cognitive impairment (MCI). Moreover, we observed impaired ER Ca(2+) homeostasis and increased ER stress markers in PBMCs from MCI individuals and mild AD patients. Evidence of early oxidative stress defense mechanisms in AD was substantiated by increased p(Ser40)Nrf2 in 3 month-old 3xTg-AD male mice PBMCs, and also with increased nuclear Nrf2 levels in brain cortex. However, SOD1 protein levels were decreased in human MCI PBMCs and in 3xTg-AD mice brain cortex; the latter further correlated with reduced SOD1 mRNA levels. Increased ER stress was also detected in the brain cortex of young female and old male 3xTg-AD mice. We demonstrate oxidative stress and early Nrf2 activation in AD human and mouse models, which fails to regulate some of its targets, leading to repressed expression of antioxidant defenses (e.g. SOD-1), and extending to ER stress. Results suggest markers of prodromal AD linked to oxidative stress associated with Nrf2 activation and ER stress that may be followed in human peripheral blood mononuclear cells. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 04/2015; 1852(7). DOI:10.1016/j.bbadis.2015.03.015 · 4.66 Impact Factor
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    • "As a matter of fact, UPR ER activation markers have been extensively documented in postmortem brain tissue from AD subjects and in animal and in vitro models of the disease (Hoozemans et al., 2009, 2012). Enhanced autophagy with the concomitant increase in LC3 levels was documented in AD neurons displaying UPR activation, pinpointing autophagy as a major degradative pathway upon UPR activation (Nijholt et al., 2011; Scheper et al., 2011). Moreover, it was observed that ER dysfunction and subsequent cell death triggered by Ab is correlated with the induction of autophagy (Lai et al., 2009). "
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    ABSTRACT: Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.
    DNA and Cell Biology 02/2015; 34(4). DOI:10.1089/dna.2014.2757 · 1.99 Impact Factor
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    • "ERAD is directly affected by the UPR, for example activation of the UPR increases the levels of EDEM1, which changes the recognition of aberrant proteins (Ron et al., 2011). Activation of the UPR also triggers autophagy (Bernales et al., 2006; Ding et al., 2007; Ogata et al., 2006) and our group previously showed that during UPR activation autophagy is the major degradational pathway (Nijholt et al., 2011a; Scheper et al., 2011). It is possible that, under these stress conditions, parts of the ER are directly targeted for clearance by the autophagy/lysosomal system (Bernales et al., 2007). "
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    ABSTRACT: Disturbances in proteostasis are observed in many neurodegenerative diseases. This leads to activation of protein quality control to restore proteostasis, with a key role for the removal of aberrant proteins by proteolysis. The unfolded protein response (UPR) is a protein quality control mechanism of the endoplasmic reticulum (ER) that is activated in several neurodegenerative diseases. Recently we showed that the major proteolytic pathway during UPR activation is via the autophagy/lysosomal system. Here we investigate UPR induction if the other major proteolytic pathway of the ER -ER associated degradation (ERAD)-is inhibited. Surprisingly, impairment of ERAD results in decreased UPR activation and protects against ER stress toxicity. Autophagy induction is not affected under these conditions, however, a striking relocalization of the lysosomes is observed. Our data suggest that a protective UPR-modulating mechanism is activated if ERAD is inhibited, which involves lysosomes. Our data provide insight in the cross-talk between proteolytic pathways involved in ER proteostasis. This has implications for neurodegenerative diseases like Alzheimer's disease where disturbed ER proteostasis and proteolytic impairment are early phenomena in the pathology.
    Moleculer Cells 03/2013; 35(4). DOI:10.1007/s10059-013-2286-9 · 2.24 Impact Factor
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