Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport
Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport
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DOI：
10.1016/j.celrep.2021.108971
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发表时间：
2021-04-13
期刊：
影响因子：
8.8
通讯作者：
Hirokawa, Nobutaka
中科院分区：
文献类型：
--
作者：
Yoshihara, Shogo;Jiang, Xuguang;Hirokawa, Nobutaka
在精神分裂症（SCZ）中，大脑中的神经元往往会发生总体形态学变化，但相关的分子机制在很大程度上仍然难以捉摸。使用Kif 3b（+/-）小鼠作为具有SCZ样行为的模型，我们发现高甜菜碱饮食可以显著减轻与神经元形态发生和行为相关的精神分裂症特征。根据KIF 3马达对神经生长素反应介导蛋白2（CRMP 2）转运的缺陷，我们确定了发育中Kif 3b（+/-）神经元的板状脂质动力学的显著减少是神经突超分支的原因。甜菜碱给药显著降低CRMP 2羰基化，这增强了适当的片状伪足动力学和微管排斥所需的F-肌动蛋白捆绑，因此可以在功能上补偿KIF 3缺乏。由于KIF 3的表达水平在SCZ患者死后大脑的人类前额叶皮层中倾向于下调，因此这种机制可能部分参与了人类SCZ的发病机制，我们假设甜菜碱给药可以减轻这种机制。
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.