Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis

Life Sci Alliance. 2019 Oct 7;2(5):e201900478. doi: 10.26508/lsa.201900478. Print 2019 Oct.


Enhanced carbonyl stress underlies a subset of schizophrenia, but its causal effects remain elusive. Here, we elucidated the molecular mechanism underlying the effects of carbonyl stress in iPS cells in which the gene encoding zinc metalloenzyme glyoxalase I (GLO1), a crucial enzyme for the clearance of carbonyl stress, was disrupted. The iPS cells exhibited significant cellular and developmental deficits, and hyper-carbonylation of collapsing response mediator protein 2 (CRMP2). Structural and biochemical analyses revealed an array of multiple carbonylation sites in the functional motifs of CRMP2, particularly D-hook (for dimerization) and T-site (for tetramerization), which are critical for the activity of the CRMP2 tetramer. Interestingly, carbonylated CRMP2 was stacked in the multimer conformation by irreversible cross-linking, resulting in loss of its unique function to bundle microtubules. Thus, the present study revealed that the enhanced carbonyl stress stemmed from the genetic aberrations results in neurodevelopmental deficits through the formation of irreversible dysfunctional multimer of carbonylated CRMP2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation
  • Cells, Cultured
  • Frameshift Mutation*
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Intercellular Signaling Peptides and Proteins / chemistry*
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lactoylglutathione Lyase / genetics*
  • Mass Spectrometry
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism*
  • Protein Carbonylation
  • Protein Conformation
  • Protein Multimerization
  • Schizophrenia / genetics*
  • Schizophrenia / metabolism


  • Intercellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • collapsin response mediator protein-2
  • GLO1 protein, human
  • Lactoylglutathione Lyase

Associated data

  • PDB/5MKV
  • PDB/6JV9
  • PDB/6JVB