title: Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders.
abstract: Fragile X mental retardation protein (FMRP) is an RNA binding protein with 842 target mRNAs in mammalian brain. Silencing of the fragile X mental retardation 1 (FMR1) gene leads to loss of expression of FMRP and upregulated metabotropic glutamate receptor 5 (mGluR5) signaling resulting in the multiple physical and cognitive deficits associated with fragile X syndrome (FXS). Reduced FMRP expression has been identified in subjects with autism, schizophrenia, bipolar disorder, and major depression who do not carry the mutation for FMR1. Our laboratory has recently demonstrated altered expression of four downstream targets of FMRP-mGluR5 signaling in brains of subjects with autism: homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP). In the current study we investigated the expression of the same four proteins in lateral cerebella of subjects with schizophrenia, bipolar disorder, and major depression and in frontal cortex of subjects with schizophrenia and bipolar disorder. In frontal cortex we observed: 1) reduced expression of 120 kDa form of APP in subjects with schizophrenia and bipolar disorder; 2) reduced expression of 61 kDa and 33k Da forms of STEP in subjects with schizophrenia; 3) reduced expression of 88 kDa form of APP in subjects with bipolar disorder; and 3) trends for reduced expression of 88 kDa form of APP and homer 1 in subjects with schizophrenia and bipolar disorder, respectively. In lateral cerebella there was no group difference, however we observed increased expression of RAC1 in subjects with bipolar disorder, and trends for increased RAC1 in subjects with schizophrenia and major depression. Our results provide further evidence that proteins involved in the FMRP-mGluR5 signaling pathway are altered in schizophrenia and mood disorders.
authors.affiliation: Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, United States. Electronic address: folso013@umn.edu.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Folsom
authors.affiliation: VA Medical Center, Department of Psychiatry, 1 Veterans Drive Minneapolis, MN 55417-2399, United States. Electronic address: pthuras@gmail.com.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thuras
authors.affiliation: Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, 420 Delaware St. SE, MMC 392, Minneapolis, MN 55455, United States; Department of Neuroscience, University of Minnesota Medical School, 321 Church St. SE, Minneapolis, MN 55455, United States. Electronic address: fatem002@umn.edu.
authors.forename: S Hossein
authors.initials: SH
authors.lastname: Fatemi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001921:Brain / Q000378:metabolism*; D015331:Cohort Studies; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D019964:Mood Disorders / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism; D018085:Regulon / Q000235:genetics; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D010751:Phosphopyruvate Hydratase; D053764:Presenilin-1; D017027:Protein Tyrosine Phosphatases; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; C578935:GRM5 protein, human; C508853:PSEN1 protein, human
keywords: APP; RAC1; STEP; bipolar disorder; homer 1; schizophrenia