1. Betaine ameliorates schizophrenic traits by functionally compensating for KIF3-based CRMP2 transport.
- Author
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Yoshihara S, Jiang X, Morikawa M, Ogawa T, Ichinose S, Yabe H, Kakita A, Toyoshima M, Kunii Y, Yoshikawa T, Tanaka Y, and Hirokawa N
- Subjects
- Actins genetics, Actins metabolism, Animals, Behavior, Animal drug effects, Biological Transport, Diet methods, Disease Models, Animal, Gene Expression Regulation, Developmental, Humans, Intercellular Signaling Peptides and Proteins deficiency, Kinesins deficiency, Male, Mice, Mice, Knockout, Microtubules drug effects, Microtubules metabolism, Microtubules ultrastructure, Nerve Tissue Proteins deficiency, Neurons metabolism, Neurons ultrastructure, Prefrontal Cortex metabolism, Prefrontal Cortex pathology, Protein Binding, Protein Carbonylation, Pseudopodia metabolism, Pseudopodia ultrastructure, Schizophrenia genetics, Schizophrenia metabolism, Schizophrenia pathology, Betaine pharmacology, Intercellular Signaling Peptides and Proteins genetics, Kinesins genetics, Nerve Tissue Proteins genetics, Neurons drug effects, Prefrontal Cortex drug effects, Pseudopodia drug effects, Schizophrenia diet therapy
- 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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