Cell Reports 35巻 2号、2021年4月13日

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, and Nobutaka Hirokawa

Abstract

Neurons in schizophrenia (SCZ) brains tend to undergo gross morphological changes, but its molecular mechanism is still largely elusive. Using Kif3b^+/- mice as a SCZ model, here we show that high betaine diet can significantly remedy their schizophrenic traits in neuronal morphogenesis and social behavior. We identified significant reduction and restoration by betaine of lamellipodial dynamics in developing Kif3b^+/- neurons as a cause of neurite hyperbranching, according to a local deficiency of collapsin response mediator protein 2 (CRMP2) transported by the KIF3 motor. Betaine administration significantly decreased the CRMP2 carbonylation, which enhanced its F-actin bundling activity necessary for proper lamellipodial dynamics and peripheral microtubule exclusion, and thus may functionally compensate the KIF3 deficiency. Because KIF3 expression levels tended to be downregulated in human prefrontal cortex of postmortem SCZ patient brains, this mechanism may also take part in human SCZ pathogenesis, which we propose will be remedied by betaine administration.

Keywords: schizophrenia, betaine, CRMP2 carbonylation, actin dynamics, kinesin, neurite hyperbranching

AMED Press Release 「ベタインはキネシン分子モーターの機能低下による統合失調症様の症状を改善する
－KIF3分子モーターはCRMP2タンパク質を輸送し、ベタインはCRMP2タンパク質のアクチン束化能を改善し神経細胞の形態を整える－」 https://www.amed.go.jp/news/release_20210414-02.html