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Review: Modulating the Unfolded Protein Response to Prevent Neurodegeneration and Enhance Memory

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Review: Modulating the Unfolded Protein Response to Prevent Neurodegeneration and Enhance Memory Neuropathology and Applied Neurobiology (2015), 41, 414–427 doi: 10.1111/nan.12211 Review: Modulating the unfolded protein response to prevent neurodegeneration and enhance memory M. Halliday* and G. R. Mallucci*† *MRC Toxicology Unit, Hodgkin Building, University of Leicester, Leicester, and †Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, UK M. Halliday and G. R. Mallucci (2015) Neuropathology and Applied Neurobiology 41, 414–427 Modulating the unfolded protein response to prevent neurodegeneration and enhance memory Recent evidence has placed the unfolded protein response heimer’s, Parkinson’s, tauopathies and prion diseases. (UPR) at the centre of pathological processes leading to Protein synthesis is also an essential step in the formation neurodegenerative disease. The translational repression of new memories. Restoring translation in disease or caused by UPR activation starves neurons of the essential increasing protein synthesis from basal levels has been proteins they need to function and survive. Restoration of shown to improve memory in numerous models. As protein synthesis, via genetic or pharmacological means, is neurodegenerative diseases often present with memory neuroprotective in animal models, prolonging survival. impairments, targeting the UPR to both provide This is of great interest due to the observation of UPR neuroprotection and enhance memory provides an activation in the post mortem brains of patients with Alz- extremely exciting novel therapeutic target. Keywords: memory, neurodegeneration, neurodegenerative diseases, therapeutics, unfolded protein response misfolding disorders [1]. At the molecular level, abnor- Introduction: the protein misfolding disorders mally folded proteins include oligomers, aggregates or The development of disease-modifying therapies for large-protein inclusions. A great deal of research effort neurodegenerative diseases remains one of the biggest has been directed to unraveling how each individual challenges facing society worldwide. As life expectancy ‘toxic’ protein exerts its deleterious effects in specific dis- increases, a concurrent rise in neurodegenerative dis- eases, but to date, mechanistic insights into how these eases is occurring globally as the population ages. These cause neuronal loss has been limited and consequently disorders, which include Alzheimer’s disease (AD), Par- therapeutic advances have been elusive. kinson’s disease (PD), frontotemporal dementia (FTD) AD is the most common cause of dementia and is and tauopathies, as well as amyotrophic lateral sclerosis characterized by episodic memory loss, progressive cog- (ALS) and prion diseases, have distinct clinical, patho- nitive impairment and behavioural changes. Pathologi- logical and biochemical signatures, and all involve the cally, amyloid plaques and neurofibrillary tangles are accumulation of disease-specific misfolded proteins in seen in post mortem brains. Amyloid plaques are mainly the brain. They are now collectively termed protein composed of amyloid-β (Aβ) peptides, typically 1–40 and 1–42 amino acids in size, that are produced from the Correspondence: Giovanna R. Mallucci, University of Cambridge, cleavage of the amyloid precursor protein (APP) by Clinical Neurosciences, Clifford Allbut Building, Addenbrooke’s Hos- secretases [2]. Hyperphosphorylated tau protein misfolds pital Cambridge Biomedical Campus, Cambridge CB2 OHN, UK. Tel: +44 (0)116 252 5550; Fax: +44 (0)116 252 5616; E-mail: grm7@ and aggregates to form neurofibrillary tangles [3]. PD is le.ac.uk characterized by extra-pyramidal motor symptoms and 414 © 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. UPR in neurodegeneration and memory 415 signs, caused by the loss of dopaminergic neurons in the the different cellular processes by which many proteins are substantia nigra with variable dementia [4]. Aggregated synthesized, folded, modified and transported to their α-synuclein is the major component of Lewy bodies, intended destinations. Disturbance in the function of the abnormal aggregates of protein that are characteristic of ER leads to ER stress and is usually caused by accumula- PD [5]. ALS is a progressive paralytic disease, involving tion of unfolded proteins and by changes in calcium the selective degeneration of motor neurons in the homeostasis within the ER [17]. In neurodegenerative dis- central and peripheral nervous systems that eventually eases, many of the cellular processes controlled by the ER leads to breathing failure. Several misfolded proteins can be disrupted by the disease pathology, causing stress have been linked to ALS, including superoxide dismutase that contributes and exacerbates neuronal cell death [16]. 1 (SOD1), TAR DNA-binding protein 43 KDa (TDP-43) The cell’s main weapon against ER stress is induction of and fused in sarcoma [6]. The prototypic, but rarest, of the unfolded protein response (UPR), which has recently these disorders are the prion diseases, which include emerged as an extremely interesting and attractive thera- Creutzfeldt–Jakob disease (CJD). These are characterized peutic target [18], due to its role in memory and clinically by rapidly progressive dementia and movement neurodegeneration. disorders, and pathologically by spongiform degeneration of the brain and the accumulation of protease-resistant The UPR prion protein (PrP) [7]. It is increasingly clear that this group of diseases have The UPR is a protective cellular response induced during common features as well as specific characteristics. Prion periods of ER stress that aims to reduce unfolded diseases are transmissible, and the mechanism of infec- protein load and restore protein-folding homeostasis, tivity and spread involves conversion of native PrP (PrPC) ‘proteostasis’. Secreted and transmembrane proteins enter by the misfolded form, termed PrPSc, via an auto-catalytic the ER as unfolded proteins to be properly assembled or to post-translational change in conformation. As neurons be targeted for degradation [19]. During ER stress, proteins become depleted of PrPC, newly synthesized PrPC is pro- inside the ER lumen waiting to be folded and exported build duced, providing additional substrate for the conversion. up, causing a backlog that is stressful to the cell. This is PrPSc can spread between neurons, gradually increasing detected by binding immunoglobulin protein (BiP), which the area of the brain affected, or between organisms if binds to exposed hydrophobic domains of unfolded pro- infected material is ingested or transferred by iatrogenic teins [20]. The UPR has three arms (Figure 1), which initi- exposure. It is now apparent that Aβ, tau and ates signalling cascades through protein kinase RNA α-synuclein are capable of the spreading templated (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1 conformational change first described for prions. It has (IRE1) and activating transcription factor 6 (ATF6) [18]. been shown that this can cause spread between cells in BiP holds these proteins in an inactive state until it binds vitro [8–10] and also in mouse models, where spread of unfolded proteins and dissociates, allowing their activa- these proteins can cause regional pathology and disease tion. The cells’ first response to ER stress is to attenuate progression [11–13]. Recently, the propagation of wild- further protein synthesis until the unfolded protein type α-synuclein causing sporadic phenotypes has been backlog is removed. This is controlled by PERK, which reported, as has transmission between animals [13,14]. when freed from BiP, dimerizes and autophosphorylates However, despite the universality of the prion-like [21]. Phosphorylated PERK (PERK-P) will then phosphor- spreading phenomenon, not all of these models show ylate eIF2α, rapidly and potently attenuating translation associated neurodegeneration, especially when trans- [22]. eIF2α is a vital component of ternary complex, which ferred between animals [15]. Nevertheless, this raises the loads mRNA onto the ribosome during the initiation of concept that protein misfolding disorders have two translation [23]. The energy for this reaction is supplied in aspects, cell autonomous processes that cause cellular the form of guanosine-5′-triphosphate (GTP) by eIF2B. dysfunction and neurodegeneration, and non-cell Phosphorylated eIF2α (eIF2α-P) binds so tightly to eIF2B autonomous processes through which the misfolded pro- that it can no longer recycle GTP,and due to the overabun- teins, and pathology, spreads. danceof eIF2αcomparedwitheIF2B,evenasmallincrease Another common theme in these disorders is in eIF2α-P will greatly inhibit ternary complex formation endoplasmic reticulum (ER) stress [16]. The ER controls and hence translation [23]. © 2014 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd NAN 2015; 41: 414–427 on behalf of British Neuropathological Society 416 M. Halliday and G. R. Mallucci cellular stress UPR PKR GCN2 PERK IRE1α ATF6 PP PP salubrinal P GSK2606414 XBP1 nATF6 eIF2α eIF2α P GADD34 ISRIB upregulation of UPR target genes ATF4 reduced protein sythesis CHOP memory impairment and neurodegeneration Figure 1. UPR and ISR signalling through
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