Sex-specific proteomic changes induced by genetic deletion of fibroblast growth factor 14 (FGF14), a regulator of neuronal ion channels

Mark L. Sowers, Jessica Di Re, Paul A. Wadsworth, Alexander S. Shavkunov, Cheryl Lichti, Kangling Zhang, Fernanda Laezza

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14-/- mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14-/- model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from Fgf14+/+ and Fgf14-/- mice. We discovered that all of the differentially expressed proteins measured in Fgf14-/- animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male Fgf14-/- mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14-/- mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14-/- mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy.

Original languageEnglish (US)
Article number5
JournalProteomes
Volume7
Issue number1
DOIs
StatePublished - Mar 1 2019

Keywords

  • Alzheimer's Disease
  • Autism
  • Bioinformatics
  • Cognitive impairment
  • Excitatory/inhibitory tone
  • FGF14
  • Mass spectroscopy
  • Schizophrenia
  • Sex-specific differences
  • Synaptic plasticity
  • Voltage gated channels

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'Sex-specific proteomic changes induced by genetic deletion of fibroblast growth factor 14 (FGF14), a regulator of neuronal ion channels'. Together they form a unique fingerprint.

  • Cite this