title: Sustained translational repression by eIF2α-P mediates prion neurodegeneration.
abstract: The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the α-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2α-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2α-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2α-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2α-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2α-P dephosphorylation, increased eIF2α-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.
authors.affiliation: MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Moreno
authors.forename: Helois
authors.initials: H
authors.lastname: Radford
authors.forename: Diego
authors.initials: D
authors.lastname: Peretti
authors.forename: Joern R
authors.initials: JR
authors.lastname: Steinert
authors.forename: Nicholas
authors.initials: N
authors.lastname: Verity
authors.forename: Maria Guerra
authors.initials: MG
authors.lastname: Martin
authors.forename: Mark
authors.initials: M
authors.lastname: Halliday
authors.forename: Jason
authors.initials: J
authors.lastname: Morgan
authors.forename: David
authors.initials: D
authors.lastname: Dinsdale
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Ortori
authors.forename: David A
authors.initials: DA
authors.lastname: Barrett
authors.forename: Pavel
authors.initials: P
authors.lastname: Tsaytler
authors.forename: Anne
authors.initials: A
authors.lastname: Bertolotti
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.forename: Martin
authors.initials: M
authors.lastname: Bushell
authors.forename: Giovanna R
authors.initials: GR
authors.lastname: Mallucci
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D015852:Eukaryotic Initiation Factor-2 / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D018620:PrPSc Proteins / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D017096:Prion Diseases / Q000473:pathology; D011328:Prions / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000502:physiology
chemical_list: D002934:Cinnamates; D015852:Eukaryotic Initiation Factor-2; D018696:Neuroprotective Agents; D010750:Phosphoproteins; D018620:PrPSc Proteins; D011328:Prions; D012097:Repressor Proteins; C496827:salubrinal; D054645:Protein Phosphatase 1; D013890:Thiourea