Impaired selenoprotein expression in brain triggers striatal neuronal loss leading to co-ordination defects in mice

Biochem J. 2014 Aug 15;462(1):67-75. doi: 10.1042/BJ20140423.

Abstract

Secisbp2 [SECIS (selenocysteine insertion sequence)-binding protein 2] binds to SECIS elements located in the 3'-UTR region of eukaryotic selenoprotein mRNAs. It facilitates the incorporation of the rare amino acid selenocysteine in response to UGA codons. Inactivation of Secisbp2 in hepatocytes greatly reduced selenoprotein levels. Neuron-specific inactivation of Secisbp2 (CamK-Cre; Secisbp2fl/fl) reduced cerebral expression of selenoproteins to a lesser extent than inactivation of tRNA[Ser]Sec. This allowed us to study the development of cortical PV (parvalbumin)+ interneurons, which are completely lost in tRNA[Ser]Sec mutants. PV+ interneuron density was reduced in the somatosensory cortex, hippocampus and striatum. In situ hybridization for Gad67 (glutamic acid decarboxylase 67) confirmed the reduction of GABAergic (where GABA is γ-aminobutyric acid) interneurons. Because of the obvious movement phenotype involving a broad dystonic gait, we suspected basal ganglia dysfunction. Tyrosine hydroxylase expression was normal in substantia nigra neurons and their striatal terminals. However the densities of striatal PV+ and Gad67+ neurons were decreased by 65% and 49% respectively. Likewise, the density of striatal cholinergic neurons was reduced by 68%. Our observations demonstrate that several classes of striatal interneurons depend on selenoprotein expression. These findings may offer an explanation for the movement phenotype of selenoprotein P-deficient mice and the movement disorder and mental retardation described in a patient carrying SECISBP2 mutations.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / metabolism*
  • Glutamate Decarboxylase / biosynthesis
  • Interneurons / physiology*
  • Mice
  • Movement Disorders / genetics
  • Parvalbumins / biosynthesis
  • RNA-Binding Proteins / genetics*
  • Selenocysteine / metabolism
  • Selenoproteins / biosynthesis*
  • Somatosensory Cortex / metabolism

Substances

  • Parvalbumins
  • RNA-Binding Proteins
  • SECIS-binding protein 2, mouse
  • Selenoproteins
  • Selenocysteine
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1