Update on the Pathophysiology of Prion Diseases
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ACNRSO14_Layout 1 04/09/2014 22:13 Page 6 REVIEW ARTICLE Update on the Pathophysiology of Prion Diseases extensive neuronal cell loss. Whilst PrP Sc is asso - Summary ciated with infectivity (prion diseases are trans - • Prion diseases are characterised by the missible), there is extensive evidence that it is not accumulation of misfolded prion protein in itself neurotoxic. Sub-clinical states of prion (PrP) and widespread neuronal loss disease have been identified in which extensive throughout the brain. Recent work has accumulation of PrP Sc is dissociated from neuro - elucidated a major mechanism by which toxicity. 3 PrP Sc is harmless to cells devoid of PrP C, misfolded PrP induces neurodegeneration and therapeutic agents targeting PrP Sc have very in prion disease. limited efficacy and do not prevent neuronal • Rising levels of misfolded PrP lead to C Giovanna Mallucci loss. PrP is absolutely required for susceptibility sustained dysregulation of an endogenous to prion neurotoxicity: PrP-null mice are resistant is Professor of Neuroscience and cellular pathway, the unfolded protein Programme Leader at the MRC to prion disease 4 and depleting PrP C in neurons response (UPR), which regulates protein Toxicology Unit and Honorary of prion infected mice cures disease, as conver - Consultant Neurologist at synthesis at the level of translation sion can no longer occur. 5 Thus, the process of Addenbrooke's Hospital, with a initiation. prion protein misfolding is central to neurotoxi - specialist interest in dementia. She • This results in the sustained reduction in city. Recent work has shown that neuronal death gained her PhD in 2001 from Imperial global protein synthesis rates in neurons, College, London, developing a new leading to loss of critical proteins, results from dysregulation of the cellular transgenic model of 'reversible’ prion response to unfolded proteins triggered by the disease, after which she combined resulting in synaptic failure and neuronal 6 scientific and clinical careers focused death. process of prion protein misfolding. on understanding generic • Genetic and pharmacological mechanisms of neurodegeneration. manipulation of this pathway to restore The Unfolded Protein Response protein synthesis prevents neuronal loss, All cells need correctly folded proteins for reverses cognitive deficits and abrogates normal functioning. The build up of unfolded clinical disease. proteins within the endoplasmic reticulum (ER) • The same branch of the UPR is over- constitutes a form of cellular stress that elicits a activated in other protein misfolding protective signalling cascade, the Unfolded disorders, including Alzheimer’s and Protein Response (UPR), which maintains Parkinson’s diseases, ALS and PSP. Further, protein-folding homeostasis, “proteostasis”. 7 it is a key pathway in learning and Rising levels of misfolded proteins in the ER are memory. Therefore, UPR modulation to detected by Binding immunoglobulin protein restore protein synthesis levels in neurons (BiP), which results in activation of the three is potentially an important new Nicholas Verity branches of the UPR to increase protein folding is a PhD student at the MRC therapeutic strategy for through chaperone expression (via ATF6 and Toxicology Unit in Leicester. He is neurodegenerative disease. primarily interested in translational IRE1 branches) and to transiently reduce protein changes in the brain during the levels by inhibiting protein synthesis (PERK course of neurodegenerative diseases. branch). This occurs via the phosphorylation first Background of PERK and then of the alpha subunit of eIF2 Correspondence to: Giovanna Mallucci Prion diseases are rare neurodegenerative disor - (eIF2 ), which is needed for formation of Email: [email protected] ders that belong to the emerging group of ternarαy complex and initiation of translation. protein misfolding diseases, which includes Activation of the UPR is usually a transient event Conflict of interest statement: The authors declare no conflict of Alzheimer’s and Parkinson’s diseases. In each that terminates when eIF2 -P is dephosphory - interest. case, the accumulation of a disease specific lated by GADD34, rapidly reαstoring protein trans - protein is associated with a relatively stereotyped lation. 8 Provenance and peer review: clinicopathological syndrome. How neuronal Commissioned and externally reviewed. loss occurs in these disorders is not clear, but The UPR in prion disease recent work has revealed the mechanism by Recent work in prion diseased mice revealed To cite: which protein misfolding leads to neurodegener - that rising levels of misfolded prion protein Mallucci G, Verity N. ation in prion disease. caused and sustained increase in the phosphory - ACNR 2014;14(4):6-8. The central pathogenic process in prion disor - lation of PERK and eIF2 in neurons. 6 The effect ders is the formation and accumulation of an of this is the sustaineαd reduction in global aberrantly folded conformer (PrP Sc ) of the host- protein synthesis rates in neurons, causing cata - encoded cellular prion protein (PrP C). 1 PrP Sc is strophic decline in levels of key proteins generated from PrP C through an autocatalytic including synaptic proteins, vital for healthy func - post-translational change in secondary structure tioning and neuronal survival. The result is (Figure 1). 2 The misfolded protein aggregates neurodegeneration. Genetic manipulation of the and accumulates throughout the brain, is accom - pathway to reduce levels of eIF2 -P restored panied by astrocytosis, spongiform change and vital protein synthesis rates and waαs profoundly 6 > ACNR > VOLUME 14 NUMBER 4 > SEPTEMBER/OCTOBER 2014 ACNRSO14_Layout 1 04/09/2014 22:14 Page 8 REVIEW ARTICLE Figure 1: Schematic of prion conversion. Native prion protein (PrP C; green partial circles) is converted into PrP Sc (black partial hexagons) in an autocatalytic process during prion replication. It is likely that PrP Sc seeds (multimers) interact with individual PrP C molecules. The two proteins have identical primary structure but differ in secondary struc - ture: PrP C is predominantly alpha helical whereas PrP Sc is rich in beta-sheet, protease resistant and accumulates, recruiting more PrP C for further cycles of conversion. Figure 2: Schematic representation of PERK exacerbating the reduction of translation) are branch of the Unfolded Protein Response (UPR) shown. b, Haematoxylin and eosin stained leading to translational repression, points of sections of CA1 region of hippocampi from intervention and neuroprotective effects. mice treated with lentiviruses mediating RNAi a, increasing levels of misfolded proteins are of PrP and GADD34 over-expression; with PERK detected by BiP in the ER, activating PERK, inhibitor GSK2606414, and salubrinal. Inhibition neuroprotective (Figure 2). This was true for upstream which autophosphorylates and in turn of UPR-mediated translational shutdown by (knockdown of PrP levels) or downstream (by lentivi - phosphorylates eIF2 , resulting in reduced shPrP, GADD34 and GSK2606414 results in rally mediated overexpression of the eIF2 -P phos - protein synthesis. Thαe points of action of marked neuroprotection with normal thickness GSK2606414 (a specific inhibitor of PERK), of of the neuronal ribbon. In contrast, worsening phatase GADD34) interventions that reduceαd eIF2 -P LV-shPrP (lentivirus mediating RNAi of PrP), of of neurodegeneration is seen with salubrinal, levels. The resultant rescue of protein synthesis raαtes LV-GADD34 (lentivirus over-expressing the which inhibits the restoration of translation. prevented decreases in synaptic protein levels, main - eIF2 -P phosphatase, GADD34) and salubrinal (Adapted from [6, 10]). tained synapse number and synaptic function, (prevαents dephosphorylation of eIF2 -P, α preventing behavioural and cognitive deficits, and resulted in extensive neuroprotection. Most importantly, there was a significant increase in survival. Notably, brains of patients with AD, PD, ALS, and the tauopathy progressive supranuclear palsy inhibiting the dephosphorylation of eIF2 -P with the (PSP), as well as prion disease. 11 Genetic polymorphisms in PERK pre-dispose to PSP. 12 small molecule salubrinal, had the oppositeα effect, exac - The pathway is also implicated in learning and memory; manipulation of eIF2 -P erbating the decrease in protein synthesis and acceler - levels boost cognition in wild type mice and restore memory deficits in AD moαuse ating disease. Critically, this rescue occurs downstream models. Thus, it would appear that targeting UPR dysregulation that occurs down - of prion replication and independently of it. PrP Sc levels stream of misfolded protein replication, be this prion, amyloid beta, tau, -synuclein are unaffected. or TDP-43 may hold promise for new treatments for neurodegenerativαe disorders more broadly. N Pharmacological modulation of the UPR in prion disease These data led to the prediction that pharmacological inhibition of PERK- eIF2 -P signalling would be similarly REFERENCES neuroprotective. GSK26α06414, a highly selective PERK 9 inhibitor, was orally administered to prion-infected 1. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science 1982;216(4542):136-44. mice daily from points both before and after the onset of 2. Prusiner SB. Creutzfeldt-Jakob disease and scrapie prions. Alzheimer Dis Assoc Disord 1989;3(1-2):52-78. behavioural deficits. 10 PERK inhibition by GSK2606414 3. Hill AF, Collinge J. Subclinical prion infection in humans and animals.