Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels
by
Mark L. Sowers 1,2,†, Jessica Di Re 2,3,†
, Paul A. Wadsworth 1,2,4, Alexander S. Shavkunov 2, Cheryl Lichti 2, Kangling Zhang 2 and Fernanda Laezza 2,*
Mark L. Sowers 1,2,†, Jessica Di Re 2,3,†, Paul A. Wadsworth 1,2,4, Alexander S. Shavkunov 2, Cheryl Lichti 2, Kangling Zhang 2 and Fernanda Laezza 2,*
1
UTMB MD/PhD Combined Degree Program, University of Texas Medical Branch, Galveston, TX 77555, USA
2
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
3
Neuroscience Graduate Program, University of Texas Medical Branch, Galveston, TX 77555, USA
4
Biochemistry and Molecular Biology Graduate Program, University of Texas Medical Branch, Galveston, TX 77555, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally.
Proteomes 2019, 7(1), 5; https://doi.org/10.3390/proteomes7010005
Received: 16 November 2018 / Revised: 16 January 2019 / Accepted: 17 January 2019 / Published: 23 January 2019
(This article belongs to the Special Issue Neuroproteomics)
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.
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Keywords:
mass spectroscopy; bioinformatics; FGF14; voltage gated channels; schizophrenia; autism; Alzheimer’s Disease; sex-specific differences; synaptic plasticity; cognitive impairment; excitatory/inhibitory tone
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MDPI and ACS Style
Sowers, M.L.; Di Re, J.; Wadsworth, P.A.; Shavkunov, A.S.; Lichti, C.; Zhang, K.; Laezza, F. Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels. Proteomes 2019, 7, 5.
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