Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport

Shogo Yoshihara, Xuguang Jiang, Momo Morikawa, Tadayuki Ogawa, Sotaro Ichinose, Hirooki Yabe, Akiyoshi Kakita, Manabu Toyoshima, Yasuto Kunii, Takeo Yoshikawa, Yosuke Tanaka, Nobutaka Hirokawa

Research output: Contribution to journalArticlepeer-review

Abstract

In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b+/− mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b+/− neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.

Original languageEnglish
Article number108971
JournalCell Reports
Volume35
Issue number2
DOIs
Publication statusPublished - 2021 Apr 13

Keywords

  • actin dynamics
  • betaine
  • carbonylation
  • CRMP2
  • KIF3
  • kinesin
  • lamellipodia
  • neurite branching
  • schizophrenia
  • social interaction

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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