Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3.
Recent studies have identified disrupted-in-schizophrenia-1 (DISC1) as a strong genetic risk factor associated with schizophrenia. Previously, we have reported that a mutation in the second exon of the DISC1 gene [leucine to proline at amino acid position 100, L100P] leads to the development of schizophrenia-related behaviors in mice. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase that interacts with the N-terminal region of DISC1 (aa 1-220) and has been implicated as an important downstream component in the etiology of schizophrenia. Here, for the first time, we show that pharmacological and genetic inactivation of GSK-3 reverse prepulse inhibition and latent inhibition deficits as well as normalizing the hyperactivity of Disc1-L100P mutants. In parallel to these observations, interaction between DISC1 and GSK-3α and β is reduced in Disc1-L100P mutants. Our data provide genetic, biochemical, and behavioral evidence for a molecular link between DISC1 and GSK-3 in relation to psychopathology and highlights the value of missense mutations in dissecting the underlying and complex molecular mechanisms of neurological disorders.
Lipina
Tatiana V
TV
Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada. lipina@lunenfeld.ca
Kaidanovich-Beilin
Oksana
O
Patel
Satish
S
Wang
Min
M
Clapcote
Steven J
SJ
Liu
Fang
F
Woodgett
James R
JR
Roder
John C
JC
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism*
C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D038362:Glycogen Synthase Kinase 3