Failure to support a genetic contribution of AKT1 polymorphisms and altered AKT signaling in schizophrenia.
The protein kinase v-akt murine thymoma viral oncogene homolog (AKT) gene family comprises three human homologs that phosphorylate and inactivate glycogen synthase kinase 3beta (GSK3beta). Studies have reported the genetic association of AKT1 with schizophrenia. Additionally, decreased AKT1 protein expression and the reduced phosphorylation of GSK3beta were reported in this disease, leading to a new theory of attenuated AKT1-GSK3beta 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 GSK3beta detected in the schizophrenic brains from two different brain banks also failed to support the theory. In addition, no attenuated AKT-GSK3beta signaling was observed in the lymphocytes from Japanese schizophrenics, contrasting with previous findings. Importantly, we found that the level of phosphorylated GSK3beta 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 GSK3beta and AKT in postmortem brains. Collectively, this study failed to support reduced signaling of the AKT-GSK3beta molecular cascade in schizophrenia.
Ide
Masayuki
M
Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan.
Ohnishi
Tetsuo
T
Murayama
Miyuki
M
Matsumoto
Izuru
I
Yamada
Kazuo
K
Iwayama
Yoshimi
Y
Dedova
Irina
I
Toyota
Tomoko
T
Asada
Takashi
T
Takashima
Akihiko
A
Yoshikawa
Takeo
T
D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007564:Japan; D008214:Lymphocytes / Q000201:enzymology; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012559:Schizophrenia / Q000201:enzymology* / Q000235:genetics*; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics
D016875:tau Proteins; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3