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EMBO Mol Med. 2017 Aug;9(8):1100-1116. doi: 10.15252/emmm.201707723.

A normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms.

Author information

1
Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
2
Department of RNA Structure and Function, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland‡.
3
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
4
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of RNA Biology and Functional Genomics, Warsaw, Poland.
5
Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany ehrenreich@em.mpg.de m.dziembowska@cent.uw.edu.pl l.kaczmarek@nencki.gov.pl.
6
Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland ehrenreich@em.mpg.de m.dziembowska@cent.uw.edu.pl l.kaczmarek@nencki.gov.pl.
7
Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland.

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.

KEYWORDS:

Fragile X mental retardation protein; dendritic spine morphology; matrix metalloproteinase 9; phenotype‐based genetic association study; single‐nucleotide polymorphism

PMID:
28623238
PMCID:
PMC5538295
DOI:
10.15252/emmm.201707723
[Indexed for MEDLINE]
Free PMC Article

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