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1.
Cell Rep ; 35(2): 108971, 2021 04 13.
Article in English | MEDLINE | ID: mdl-33852848

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.


Subject(s)
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 , 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
2.
Life Sci Alliance ; 2(5)2019 10.
Article in English | MEDLINE | ID: mdl-31591136

ABSTRACT

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.


Subject(s)
Frameshift Mutation , Intercellular Signaling Peptides and Proteins/chemistry , Intercellular Signaling Peptides and Proteins/metabolism , Lactoylglutathione Lyase/genetics , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/metabolism , Schizophrenia/genetics , Cell Differentiation , Cells, Cultured , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Mass Spectrometry , Models, Molecular , Protein Carbonylation , Protein Conformation , Protein Multimerization , Schizophrenia/metabolism
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