PT  - JOURNAL ARTICLE
AU  - Manabu Toyoshima
AU  - Xuguang Jiang
AU  - Tadayuki Ogawa
AU  - Tetsuo Ohnishi
AU  - Shogo Yoshihara
AU  - Shabeesh Balan
AU  - Takeo Yoshikawa
AU  - Nobutaka Hirokawa
TI  - Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis
AID  - 10.26508/lsa.201900478
DP  - 2019 Oct 01
TA  - Life Science Alliance
PG  - e201900478
VI  - 2
IP  - 5
4099  - https://www.life-science-alliance.org/content/2/5/e201900478.short
4100  - https://www.life-science-alliance.org/content/2/5/e201900478.full
SO  - Life Sci. Alliance2019 Oct 01; 2
AB  - 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.