A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms
| Autor: | Hannelore Ehrenreich, Behnam Vafadari, Katarzyna Lepeta, Katarzyna Pachulska-Wieczorek, Leszek Kaczmarek, Martin Begemann, Krystian Bijata, Magdalena Dziembowska, Katarzyna J. Purzycka, Ryszard W. Adamiak, Marina Mitjans |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male Dendritic spine Adolescent single‐nucleotide polymorphism Single-nucleotide polymorphism Biology Chromatin Epigenetics Genomics & Functional Genomics Polymorphism Single Nucleotide Fragile X mental retardation protein 03 medical and health sciences Mice Young Adult dendritic spine morphology phenotype‐based genetic association study Genetic variation SNP Animals Humans RNA Messenger Gene 3' Untranslated Regions Research Articles Cells Cultured Genetic Association Studies Genetic association Aged Genetics Neurons Schizophrenia Paranoid Middle Aged Phenotype Disease Models Animal 030104 developmental biology Matrix Metalloproteinase 9 Synaptic plasticity Chronic Disease Synapses Molecular Medicine Nucleic Acid Conformation Female Genetics Gene Therapy & Genetic Disease Research Article Neuroscience Protein Binding |
| Zdroj: | EMBO Molecular Medicine |
| Popis: | 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 Gottingen 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|