Lost in Translation: Misfolded Proteins May Cause Neurodegenerationby Inhibiting Normal Protein Production

Moreno JA, Radford H, Peretti D, et al. Sustained translational repression by eIF2alpha-P mediates prionneurodegeneration. Nature. 20126;485:507–511.

One common pathophysiological mechanism underlyingmany neurodegenerative diseases is the abnormal accumu-lation and misfolding of proteins. Mechanisms to prevent orreduce such processes are thus potential therapeutic strat-egies. One such system that may be targeted is theunfolded protein response (UPR). Part of this processinvolves reduced protein translation via phosphorylation ofeukaryotic translation initiation factor (eIF2alpha). In severalneurodegenerative diseases including Parkinson’s disease,Alzheimer’s disease, and prion diseases, there is upregula-tion of this pathway and increased phosphorylation ofeIF2alpha. The mechanism whereby this change may induceneurodegeneration and ways of potentially reversing thiswere investigated in this article.The authors used a prion-infected mouse model that allows

investigation of the mechanisms involving protein misfoldingand associated neuronal loss. The authors used hemizygoustg37 mice that express prion protein (PrP) at 3-fold greaterlevels than the wild type and are infected with Rocky Moun-tain Laboratory prion infection, which causes neurodegener-ation in hippocampal neurons (synapse number, levels ofsynaptic protein, and synaptic transmission) and spongiformpathology associated with a progressive behavioral declineto death at 12 weeks. A critical time in the neurodegenera-tive process at 9 weeks was noted with a sudden decline insynaptic protein; this was associated with a rise in unfoldedproteins, leading to eIFalpha2 phosphorylation (eIF2alpha-P). There was a rise in eIFalpha2-P over the course of thedisease that paralleled a rise in PrP. The elevated eIF2alphaP reduced global protein translation by about 50%, whichcorresponded to the decline in synaptic protein. The authorsconcluded that reduced protein synthesis in prion disease is

controlled at the level of protein translation, not transcrip-tion, and the unregulated activation of UPR secondary torising levels of PrP suppresses protein translation. Transientelevation of UPR is useful, but uncontrolled persistence con-tributes to neuronal loss. This was demonstrated by reduc-ing eIF2alpha-P using a specific phosphatase (GADD34) andPrP RNAi to prevent UPR (via hippocampal injection). At9 weeks there was protection of neuronal synaptic proteinlevels and synaptic transmission in the PrP mice, equivalentto in uninfected control mice. In addition, there was markedreduction in spongiform pathology. Conversely, increasingeIF2alpha-P levels using salubrinol, a small molecule inhibi-tor of the eIF2alpha-dephosphatase, induced an accelerateddisease model compared with uninfected mice.Overall, this series of experiments demonstrates that PrP

causes sustained abnormal induction of the UPR systemand expression of eIFalpha2-P, with chronic loss of normalsynaptic protein synthesis and neuronal loss. The study wasperformed in hippocampal neurons, and thus the processin basal ganglia neurons is not yet known. Indeed, whetherthis occurs in primate brains also needs to be demon-strated. However, the implications are to explore whetherthis process occurs in other protein accumulationdiseases, for example, synuclein and amyloid, and whetherreducing eIFalpha2-P in these diseases may reduce neuro-degeneration.

Susan Fox

Movement Disorders Clinic, Toronto Western Hospital, Toronto,

Ontario, Canada

------------------------------------------------------------Relevant conflicts of interest/financial disclosures: Nothing to report.Published online in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/mds.25130

H O T T O P I C S

1218 Movement Disorders, Vol. 27, No. 10, 2012