A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms
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) i...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-06-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201707723 |
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| author | Katarzyna Lepeta Katarzyna J Purzycka Katarzyna Pachulska‐Wieczorek Marina Mitjans Martin Begemann Behnam Vafadari Krystian Bijata Ryszard W Adamiak Hannelore Ehrenreich Magdalena Dziembowska Leszek Kaczmarek |
| author_facet | Katarzyna Lepeta Katarzyna J Purzycka Katarzyna Pachulska‐Wieczorek Marina Mitjans Martin Begemann Behnam Vafadari Krystian Bijata Ryszard W Adamiak Hannelore Ehrenreich Magdalena Dziembowska Leszek Kaczmarek |
| author_sort | Katarzyna Lepeta |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-feb3d99d19e44a4dbaf612ffffbb7a49 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-feb3d99d19e44a4dbaf612ffffbb7a492025-08-20T04:03:03ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-06-01981100111610.15252/emmm.201707723A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptomsKatarzyna Lepeta0Katarzyna J Purzycka1Katarzyna Pachulska‐Wieczorek2Marina Mitjans3Martin Begemann4Behnam Vafadari5Krystian Bijata6Ryszard W Adamiak7Hannelore Ehrenreich8Magdalena Dziembowska9Leszek Kaczmarek10Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of SciencesDepartment of RNA Structure and Function, Institute of Bioorganic Chemistry, Polish Academy of SciencesDepartment of RNA Structure and Function, Institute of Bioorganic Chemistry, Polish Academy of SciencesClinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Clinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of SciencesInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of RNA Biology and Functional GenomicsDepartment of RNA Structure and Function, Institute of Bioorganic Chemistry, Polish Academy of SciencesClinical Neuroscience, Max Planck Institute of Experimental Medicine, DFG Research Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of SciencesDepartment of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of SciencesAbstract 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.https://doi.org/10.15252/emmm.201707723dendritic spine morphologyFragile X mental retardation proteinmatrix metalloproteinase 9phenotype‐based genetic association studysingle‐nucleotide polymorphism |
| spellingShingle | Katarzyna Lepeta Katarzyna J Purzycka Katarzyna Pachulska‐Wieczorek Marina Mitjans Martin Begemann Behnam Vafadari Krystian Bijata Ryszard W Adamiak Hannelore Ehrenreich Magdalena Dziembowska Leszek Kaczmarek A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms EMBO Molecular Medicine dendritic spine morphology Fragile X mental retardation protein matrix metalloproteinase 9 phenotype‐based genetic association study single‐nucleotide polymorphism |
| title | A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms |
| title_full | A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms |
| title_fullStr | A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms |
| title_full_unstemmed | A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms |
| title_short | A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms |
| title_sort | normal genetic variation modulates synaptic mmp 9 protein levels and the severity of schizophrenia symptoms |
| topic | dendritic spine morphology Fragile X mental retardation protein matrix metalloproteinase 9 phenotype‐based genetic association study single‐nucleotide polymorphism |
| url | https://doi.org/10.15252/emmm.201707723 |
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