Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model
Article first published online: 24 MAR 2014
© 2014 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Journal of Neurochemistry
Volume 129, Issue 6, pages 1002–1012, June 2014
How to Cite
J. Neurochem. (2014) 129, 1002–1012.
- Issue published online: 11 JUN 2014
- Article first published online: 24 MAR 2014
- Accepted manuscript online: 18 FEB 2014 12:24PM EST
- Manuscript Accepted: 2 FEB 2014
- Manuscript Revised: 7 JAN 2014
- Manuscript Received: 29 OCT 2013
- Ministry of Health. Grant Number: RF-2010-2318372
- Italian Ministry of University and Research. Grant Number: PONa3_00067
- Regione Campania. Grant Number: FSE 2007/2013
- altered brain proteins;
- brain proteins in PKU;
- neurological dysfunction;
- PKU mouse model
Phenylketonuria (PKU), if not detected and treated in newborns, causes severe neurological dysfunction and cognitive and behavioral deficiencies. Despite the biochemical characterization of PKU, the molecular mechanisms underlying PKU-associated brain dysfunction remain poorly understood. The aim of this study was to gain insights into the pathogenesis of this neurological damage by analyzing protein expression profiles in brain tissue of Black and Tan BRachyury-PahEnu2 mice (a mouse model of PKU). We compared the cerebral protein expression of homozygous PKU mice with that of their heterozygous counterparts using two-dimensional difference gel electrophoresis analysis, and identified 21 differentially expressed proteins, four of which were over-expressed and 17 under-expressed. An in silico bioinformatic approach indicated that protein under-expression was related to neuronal differentiation and dendritic growth, and to such neurological disorders as progressive motor neuropathy and movement disorders. Moreover, functional annotation analyses showed that some identified proteins were involved in oxidative metabolism. To further investigate the proteins involved in the neurological damage, we validated two of the proteins that were most strikingly under-expressed, namely, Syn2 and Dpysl2, which are involved in synaptic function and neurotransmission. We found that Glu2/3 and NR1 receptor subunits were over-expressed in PKU mouse brain. Our results indicate that differential expression of these proteins may be associated with the processes underlying PKU brain dysfunction, namely, decreased synaptic plasticity and impaired neurotransmission.
We identified a set of proteins whose expression is affected by hyperphenylalaninemia. We think that phenylketonuria (PKU) brain dysfunction also depends on reduced Syn2 and Dpysl2 levels, increased Glu2/3 and NR1 levels, and decreased Pkm, Ckb, Pgam1 and Eno1 levels. These findings finally confirm that alteration in synaptic function, in transmission and in energy metabolism underlie brain damage provoked by hyperphenylalaninemias.