Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia

Masayuki Ide, Tetsuo Ohnishi, Miyuki Murayama, Izuru Matsumoto, Kazuo Yamada, Yoshimi Iwayama, Irina Dedova, Tomoko Toyota, Takashi Asada, Akihiko Takashima, Takeo Yoshikawa*

*Corresponding author for this work

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3β (GSK3β). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3β were reported in this disease, leading to a new theory of attenuated AKT1-GSK3β signaling in schizophrenia pathogenesis. We have evaluated this theory by performing both genetic and protein expression analyses. A family based association test of AKT1 did not show association with schizophrenia in Japanese subjects. The expression levels of total AKT, AKT1 and phosphorylated GSK3β detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3β signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3β at Ser9 tended to be inversely correlated with postmortem intervals, and that the phosphorylation levels of AKT were inversely correlated with brain pH, issues not assessed in the previous study. These data introduce a note of caution when estimating the phosphorylation levels of GSK3β and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3β molecular cascade in schizophrenia.

Original languageEnglish
Pages (from-to)277-287
Number of pages11
JournalJournal of Neurochemistry
Volume99
Issue number1
DOIs
Publication statusPublished - Oct 2006
Externally publishedYes

Keywords

  • Association
  • Glycogen synthase kinase 3β
  • Lymphocytes
  • Phosphorylation
  • Postmortem brain
  • Western blot

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