RT Journal Article
SR Electronic
T1 Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e201900478
DO 10.26508/lsa.201900478
VO 2
IS 5
A1 Manabu Toyoshima
A1 Xuguang Jiang
A1 Tadayuki Ogawa
A1 Tetsuo Ohnishi
A1 Shogo Yoshihara
A1 Shabeesh Balan
A1 Takeo Yoshikawa
A1 Nobutaka Hirokawa
YR 2019
UL https://www.life-science-alliance.org/content/2/5/e201900478.abstract
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.