Disrupted-in-schizophrenia 1 (DISC1) regulates dysbindin function by enhancing its stability

J Biol Chem. 2015 Mar 13;290(11):7087-96. doi: 10.1074/jbc.M114.614750. Epub 2015 Jan 29.

Abstract

Dysbindin and DISC1 are schizophrenia susceptibility factors playing roles in neuronal development. Here we show that the physical interaction between dysbindin and DISC1 is critical for the stability of dysbindin and for the process of neurite outgrowth. We found that DISC1 forms a complex with dysbindin and increases its stability in association with a reduction in ubiquitylation. Furthermore, knockdown of DISC1 or expression of a deletion mutant, DISC1 lacking amino acid residues 403-504 of DISC1 (DISC1(Δ403-504)), effectively decreased levels of endogenous dysbindin. Finally, the neurite outgrowth defect induced by knockdown of DISC1 was partially reversed by coexpression of dysbindin. Taken together, these results indicate that dysbindin and DISC1 form a physiologically functional complex that is essential for normal neurite outgrowth.

Keywords: DISC1; Dysbindin; Neurite Outgrowth; Protein Complex; Protein Stability; Schizophrenia; Ubiquitylation (Ubiquitination).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Chlorocebus aethiops
  • Dysbindin
  • Dystrophin-Associated Proteins / chemistry
  • Dystrophin-Associated Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Neurites / metabolism
  • Neurites / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • Ubiquitin

Substances

  • DISC1 protein, human
  • DTNBP1 protein, human
  • Disc1 protein, mouse
  • Dtnbp1 protein, mouse
  • Dysbindin
  • Dystrophin-Associated Proteins
  • Nerve Tissue Proteins
  • Ubiquitin
  • Proteasome Endopeptidase Complex