Protein expression of targets of the FMRP regulon is altered in brains of subjects with schizophrenia and mood disorders

Timothy D. Folsom, Paul D. Thuras, S H Fatemi

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15 Scopus citations

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 33. kDa 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.

Original languageEnglish (US)
Pages (from-to)201-211
Number of pages11
JournalSchizophrenia Research
Volume165
Issue number2-3
DOIs
StatePublished - Jul 1 2015

Bibliographical note

Funding Information:
Grant support by the National Institute of Mental Health (Grant #1R01MH086000-01A2), and the Ewald Bipolar Disease Research Fund to SHF is gratefully acknowledged. (SHF). NIMH, and the Ewald Bipolar Disease Research Fund had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Funding Information:
Grant support by the National Institutes of Mental Health (Grant # 1R01MH086000-01A2 ), and the Ewald Bipolar Disease Research Fund to SHF is gratefully acknowledged. S.H. Fatemi is also supported by the Bernstein Endowed Chair in Adult Psychiatry . Tissue samples from the Stanley Medical Research Institute and assistance with demographic information from Dr. Edwin Fuller-Torrey and Dr. Maree J. Webster, to SHF is gratefully acknowledged. Tissue samples from the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number R24 MH068855 is gratefully acknowledged.

Keywords

  • APP
  • Bipolar disorder
  • Homer 1
  • RAC1
  • STEP
  • Schizophrenia

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