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

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cris.lastimport.scopus2024-02-12T19:47:10Z
dc.abstract.enMatrix 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 3untranslated 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 3UTR. 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.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorLapeta, Katarzyna
dc.contributor.authorPachulska-Wieczorek, Katarzyna
dc.contributor.authorAdamiak, Ryszard
dc.contributor.authorPurzycka, Katarzyna
dc.contributor.authorMitjans, Marina
dc.contributor.authorBegemann, Martin
dc.contributor.authorVAFADARI, BEHNAM
dc.contributor.authorBijata, Krystian
dc.contributor.authorDziembowska, Magdalena
dc.contributor.authorKACZMAREK, LESZEK
dc.contributor.authorEhrenreich, Hannelore
dc.date.accessioned2024-01-24T18:04:23Z
dc.date.available2024-01-24T18:04:23Z
dc.date.issued2017
dc.description.accesstimeBEFORE_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number8
dc.description.versionFINAL_PUBLISHED
dc.description.volume9
dc.identifier.doi10.15252/EMMM.201707723
dc.identifier.issn1757-4676
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/101738
dc.identifier.weblinkhttps://www.embopress.org/doi/full/10.15252/emmm.201707723
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofEMBO Molecular Medicine
dc.relation.pages1100-1116
dc.rightsCC-BY-ND
dc.sciencecloudnosend
dc.subject.endendritic spine morphology
dc.subject.enFragile X mental retardation protein
dc.subject.enmatrix metalloproteinase 9
dc.subject.enphenotype-based genetic association study
dc.subject.ensingle-nucleotide polymorphism
dc.titleA normal genetic variation modulates synaptic MMP-9 protein levels and the severity of schizophrenia symptoms
dc.typeJournalArticle
dspace.entity.typePublication