wortmannin reduces insulin signaling and death in seizure-prone pcmt1？？ mice渥曼青霉素减少胰岛素信号和死亡seizure-prone pcmt1 老鼠.pdfVIP

Wortmannin Reduces Insulin Signaling and Death in Seizure-Prone Pcmt1 2/ 2 Mice Kennen B. MacKay, Jonathan D. Lowenson, Steven G. Clarke* Department of Chemistry and Biochemistry and the Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America Abstract L-isoaspartyl (D-aspartyl) O-methyltransferase deficient mice (Pcmt12/ 2) accumulate isomerized aspartyl residues in intracellular proteins until their death due to seizures at approximately 45 days. Previous studies have shown that these mice have constitutively activated insulin signaling in their brains, and that these brains are 20–30% larger than those from age-matched wild-type animals. To determine whether insulin pathway activation and brain enlargement is responsible for the fatal seizures, we administered wortmannin, an inhibitor of the phosphoinositide 3-kinase that catalyzes an early step in the insulin pathway. Oral wortmannin reduced the average brain size in the Pcmt12/ 2 animals to within 6% of the wild-type DMSO administered controls, and nearly doubled the lifespan of Pcmt12/ 2 at 60% survival of the original population. Immunoblotting revealed significant decreases in phosphorylation of Akt, PDK1, and mTOR in Pcmt12/ 2 mice and Akt and PDK1 in wild-type animals upon treatment with wortmannin. These data suggest activation of the insulin pathway and its resulting brain enlargement contributes to the early death of Pcmt12/ 2 mice, but is not solely responsible for the early death observed in these animals. Citation: MacKay KB, Lowenson JD, Clarke SG (2012) Wortmannin Reduces Insulin Signaling and Death in Seizure-Prone Pcmt12/ 2 Mice. PLoS ONE 7(10): e46719. doi:10.1371/journal.pone.0046719 Editor: Shree Ram Singh, National Cancer Institute, United States of America Received July 20, 2012; Accepted Se