TY - JOUR
T1 - Sex-specific proteomic changes induced by genetic deletion of fibroblast growth factor 14 (FGF14), a regulator of neuronal ion channels
AU - Sowers, Mark L.
AU - Di Re, Jessica
AU - Wadsworth, Paul A.
AU - Shavkunov, Alexander S.
AU - Lichti, Cheryl
AU - Zhang, Kangling
AU - Laezza, Fernanda
N1 - Funding Information:
Funding: This research was funded by NIH R01MH111107 (F.L.), R01MH095995 (F.L.), R01DA047102 (F.L.), R01CA184097 (K.Z.), NIA T32 AG051131 (P.A.W.), and University of Texas Medical Branch Jeanne B. Kempner Scholarship (J.D.R.).
Publisher Copyright:
© 2019 by the authors.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
KW - Alzheimer's Disease
KW - Autism
KW - Bioinformatics
KW - Cognitive impairment
KW - Excitatory/inhibitory tone
KW - FGF14
KW - Mass spectroscopy
KW - Schizophrenia
KW - Sex-specific differences
KW - Synaptic plasticity
KW - Voltage gated channels
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U2 - 10.3390/proteomes7010005
DO - 10.3390/proteomes7010005
M3 - Article
AN - SCOPUS:85066451410
VL - 7
JO - Proteomes
JF - Proteomes
SN - 2227-7382
IS - 1
M1 - 5
ER -