Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E.
Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits.
Nat Neurosci. 2013 Sep;16(9):1299-305.
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The paper by the Klann group presents an elegant study that highlights the importance of translational control at the synapse in the pathophysiology of Amyloidβ, and perhaps, neurodegeneration generally. When Aβ causes synaptic toxicity, it necessarily causes prolonged changes at the synapse, and a large part of this occurs by modifying protein synthesis. The pathways regulating this biology represent potentially important targets for therapeutic development, yet these pathways have been largely untapped in drug discovery efforts. Klann's study demonstrated the importance of protein translation using multiple independent approaches, utilizing knockouts and inhibitors of two enzymes that act at the same hub in translational control, eIF2α.
Interestingly, Stephen Strittmatter presented a study at AD/PD 2013, which showed that Aβ increases phosphorylation of eIF2α, and does so in a manner dependent on PrP. So we now have multiple approaches coming from multiple laboratories all focusing on the same system. I'm sure that we will be hearing much more about this in the upcoming months and years.