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.