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 exciting paper by Ma et al. contributes to the accumulating evidence that PERK is involved in neurodegeneration and is potentially a therapeutic target (reviewed in (1)). Our group reported previously the activation of the unfolded protein response (UPR) in AD brain, including specific evidence for the activation of the translational PERK pathway. We detected the active form of the kinase and its phosphorylated substrate peIF2α (2,3)). This fits with the study by Ma et al.
Essentially, these authors show that interference in basic homeostatic pathways can be employed to rescue deficits in synaptic plasticity in an APP/PS1 model. The authors are rightfully cautious to translate their findings to potential treatment for human disease, as interference in homeostatic stress pathways may also have a downside.
It will be interesting to find out more mechanistic detail about the effects of PERK deletion on the progression of AD pathology, in particular tau pathology, as this is closely connected with UPR activation in human brain (3,4). Future studies will have to address how PERK deletion affects cellular stress resilience and whether and how neurons adapt to this type of interference.
Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ.
Endoplasmic reticulum dysfunction in neurological disease.
Lancet Neurol. 2013 Jan;12(1):105-18.
Hoozemans JJ, Veerhuis R, van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W.
The unfolded protein response is activated in Alzheimer's disease.
Acta Neuropathol. 2005 Aug;110(2):165-72.
Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W.
The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus.
Am J Pathol. 2009 Apr;174(4):1241-51.
Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ.
The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies.
J Pathol. 2011 Nov 21;
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.