FTO and memory - connecting the dots

FTO is a well known gene containing variants that have shown rather consistent association to obesity risk and BMI in many different populations. FTO is an efficient oxidative demethylase targeting the abundant N6-methyladenosine (m6A) residues in RNA in vitro and mRNA in the nucleus. This implies that there is a heretofore undescribed, reversible regulatory process in mammalian cells.

Late last year, it was reported that FTO variants can raise susceptibility to decline in verbal memory as detected in middle-aged, community-dwelling adults. A new report released this week has identified an inhibitor of PERK (also known as EIF2AK3) signaling that is rather potent at reversing the effects of EIF2S1 (eIF2alpha) phosphorylation. As EIF2AS1 phosphorylation is implicated in memory consolidation, it was notable that the mice treated with this inhibitor showed significant increases in spatial and fear-associated learning. Thus, the authors conclude, "memory consolidation is inherently limited by the integrated stress response (which involves PERK, PKR (EIF2AK2), GCN2 (EIF2AK4) and HRI (EIF2AK1)), and [the inhibitor] releases this brake."

Here's where things get interesting and the FTO-EIF2AK3 connection tightens. Of 77 mRNAs whose levels are either up- or down-regulated in the liver, skeletal muscle or white adipose tissue of mice homozygous for a nonsynonymous Fto point mutation, as reported by Church, et al. 2009, mRNAs from seven genes, which were all significantly up-regulated in FTO mutants, also contain methyl6A peaks: Acaca, Atf6, Bip, Gcdh, Irs1, Perk, and Xbp1 (Meyer, et al. 2012).

Data mining is fun!