salubrinal and Neurodegenerative-Diseases

The unfolded protein response, also known as endoplasmic reticulum (ER) stress, has been implicated in numerous human diseases, including atherosclerosis, cancer, diabetes, and neurodegenerative disorders. Protein misfolding activates one or more of the three ER transmembrane sensors to initiate a complex network of signaling that transiently suppresses protein translation while also enhancing protein folding and proteasomal degradation of misfolded proteins to ensure full recovery from ER stress. Gene disruption studies in mice have provided critical insights into the role of specific signaling components and pathways in the differing responses of animal tissues to ER stress. These studies have emphasized an important contribution of translational repression to sustained insulin synthesis and β-cell viability in experimental models of type-2 diabetes. This has focused attention on the recently discovered small-molecule inhibitors of eIF2α phosphatases that prolong eIF2α phosphorylation to reduce cell death in several animal models of human disease. These compounds show significant cytoprotection in cellular and animal models of neurodegenerative disorders, highlighting a potential strategy for future development of drugs to treat human protein misfolding disorders.

Topics: Animals; Atherosclerosis; Cinnamates; Diabetes Mellitus; Endoplasmic Reticulum Stress; Eukaryotic Cells; Eukaryotic Initiation Factor-2; Gene Knock-In Techniques; Guanabenz; Humans; Mice; Mice, Knockout; Mice, Transgenic; Models, Biological; Molecular Targeted Therapy; Neoplasms; Neurodegenerative Diseases; Phosphoprotein Phosphatases; Phosphorylation; Proteasome Endopeptidase Complex; Protein Biosynthesis; Protein Folding; Protein Processing, Post-Translational; Thiourea; Unfolded Protein Response

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.

Topics: Animals; Cell Death; Cinnamates; Eukaryotic Initiation Factor-2; Hippocampus; Kaplan-Meier Estimate; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Phosphoproteins; Phosphorylation; Prion Diseases; Prions; Protein Biosynthesis; Protein Folding; Protein Phosphatase 1; PrPSc Proteins; Repressor Proteins; Synapses; Synaptic Transmission; Thiourea; Unfolded Protein Response