Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3.
Synapse
; 65(3): 234-48, 2011 Mar.
Article
em En
| MEDLINE
| ID: mdl-20687111
ABSTRACT
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 ß 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Esquizofrenia
/
Quinase 3 da Glicogênio Sintase
/
Proteínas do Tecido Nervoso
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Synapse
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Canadá