24 December 2008. One of the talks that has stood out at Alzheimer research conferences this past year will appear in full in the December 26 issue of Neuron. First author Tracy O’Connor, a postdoctoral fellow in Robert Vassar’s laboratory at Northwestern University Feinberg School of Medicine in Chicago, Illinois, along with collaborators in Germany and Belgium, reports that experimentally induced deprivation in cellular energy induces phosphorylation of the translation initiation factor eIF2α. When phosphorylated, this protein then pulls away from its default function of facilitating global translation and instead drives translation of a number of stress-response genes including BACE1. Broadly speaking, in this study a range of age-related insults impinge on a common pathway of cellular energy deficiency that, when it is active chronically, increases levels of BACE1 protein and subsequently also of Aβ peptide.
Using two different mouse models, cells cultured from them, and also postmortem brain tissue from patients with AD, the scientists experimentally manipulated eIF2α phosphorylation in various ways, and then correlated its state with levels of BACE1 protein, Aβ generation, and amyloid plaque. Most data in this paper are already summarized on Alzforum following a talk at the 2008 Keystone conference.
New in the paper is the identification by O’Connor et al. of the operative kinase behind eIF2α’s change in behavior. It is none other than PKR-like ER kinase, or PERK for short. PERK is one of four known eIF2α kinases. ER stress, along with the unfolded protein response connected to it, as well as amino acid deprivation, are already well known to activate this kinase; indeed, PERK’s role in the unfolded protein response has its own established literature. To identify which kinase was at play in their model system, initially in vitro, the scientists used both genetics (i.e., kinase-dead and dominant-negative versions of the candidate enzyme genes) and pharmacology (i.e., molecular inhibitors). The scientists still need to verify whether PERK excessively phosphorylates eIF2α in the brain of AD models generally, or in people with AD or amnestic MCI.—Gabrielle Strobel.