A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms.
EMBO Mol Med
; 9(8): 1100-1116, 2017 08.
Article
em En
| MEDLINE
| ID: mdl-28623238
ABSTRACT
Matrix metalloproteinase 9 (MMP-9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype-based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP-9 rs20544 C/T single-nucleotide polymorphism (SNP) located in the 3'untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP-9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP-9 3'UTR We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP-9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis-related locomotor hyperactivity in Mmp-9 heterozygous mice. We propose a novel mechanism that involves MMP-9-dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP-9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia Paranoide
/
Sinapses
/
Metaloproteinase 9 da Matriz
/
Polimorfismo de Nucleotídeo Único
Tipo de estudo:
Diagnostic_studies
Limite:
Adolescent
/
Adult
/
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article