Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model

Esther Imperlini, Stefania Orrù, Claudia Corbo, Aurora Daniele, Francesco Salvatore

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)1002-1012
Number of pages11
JournalJournal of Neurochemistry
Volume129
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Phenylketonurias
Brain
Proteins
Synaptic Transmission
Energy Metabolism
Two-Dimensional Difference Gel Electrophoresis
Neuronal Plasticity
Bioinformatics
Electrophoresis
Movement Disorders
Metabolism
Nervous System Diseases
Computational Biology
Plasticity
Computer Simulation
Gels
Tissue

Keywords

  • altered brain proteins
  • brain proteins in PKU
  • neurological dysfunction
  • phenylketonuria
  • PKU mouse model

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Altered brain protein expression profiles are associated with molecular neurological dysfunction in the PKU mouse model. / Imperlini, Esther; Orrù, Stefania; Corbo, Claudia; Daniele, Aurora; Salvatore, Francesco.

In: Journal of Neurochemistry, Vol. 129, No. 6, 2014, p. 1002-1012.

Research output: Contribution to journalArticle

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AU - Salvatore, Francesco

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