Deficits in axon‐associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia

Shao, Li; Golbaz, Khashayar; Honer, William G.; Beasley, Clare L.

doi:10.1111/bdi.12395

Cited by 19 publications

(12 citation statements)

References 72 publications

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“…There is evidence that psychiatric disorders are connected with cytoskeletal genes by means of the transport of biological material, such as synaptic proteins along the axon. 59 , 60 The tubulin expression levels are often altered and dysfunctional in disease-specific regions such as the hippocampus and prefrontal cortex of schizophrenia and bipolar disorder patients. 61 In our paper, TPM2 is the strongest DEG followed by TAGLN among the cytoskeletal genes, and both can regulate ACTA2 .…”

Section: Discussionmentioning

confidence: 99%

Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages

et al. 2017

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Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P=2.66 × 10−10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P=3.07 × 10−19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the central nervous system. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter and cytoskeletal signalling occurs during early fetal brain development of BD I patients.

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Section: Discussionmentioning

confidence: 99%

Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages

et al. 2017

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“…Indeed, accumulating evidence suggests that abnormalities in the cytoskeleton are a potential mechanism for psychiatric illness via impaired microtubulemediated axonal transport and synaptic plasticity. 60,[71][72][73][74] It will be important to investigate how ANK3 influences microtubule-dependent processes in neurons and whether these processes underlie the association of ANK3 with psychiatric illness.…”

Section: Discussionmentioning

confidence: 99%

Disruption of The Psychiatric Risk Gene Ankyrin 3 Enhances Microtubule Dynamics Through GSK3/CRMP2 Signaling

Garza

Gjeluci

et al. 2018

Preprint

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The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specific Ank3 isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus from Ank3+/-and Ank3+/+ mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, in Ank3+/-mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons from Ank3+/-mice revealed impaired elongation of microtubules. Using a CRISPRdCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specific Ank3 increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specific Ank3 repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization in Ank3 repressed cells by lithium or CHIR99021, suggesting microtubule instability induced by Ank3 repression is dependent on CRMP2 activity. Taken together, our data indicate that ANK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/303990 doi: bioRxiv preprint first posted online Apr. 21, 2018; 3 Introduction Large-scale genomic studies are providing a clearer picture of the genetic architecture of psychiatric illness. Genetic variation in ANK3 is associated with several psychiatric disorders, including bipolar disorder (BD) and autism spectrum disorders (ASD). [1][2][3][4][5][6][7][8][9][10][11] Human postmortem brain studies demonstrate that carriers of ANK3 alleles associated with BD have lower ANK3 expression at the transcript and protein levels, 12,13 suggesting that decreased expression of ANK3 contributes to disease. Despite strong genetic evidence that ANK3 contributes to psychiatric illness 14 , the precise mechanism is unknown. ANK3 encodes the ankyrin-G scaffolding protein that anchors integral membrane proteins to the cytoskeleton. 15,16 There are several protein isoforms of ankyrin-G due to alternative splicing a...

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“…The candidate genes we selected were based on an observed difference between cases and controls, but a literature study revealed that there are also striking connections to microtubule function for several of the candidate genes, especially ANK3, NEK3, NEK7, and TUBB1. In axons, microtubules are responsible for maintaining axon structure and axonal transport 30 . Dendritic microtubules influence processes like arborization and signaling to dendritic spines 31 .…”

Section: Microtubule Function and Its Connection To Stressmentioning

confidence: 99%

Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder

et al. 2020

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Identification of causative genetic variants leading to the development of bipolar disorder (BD) could result in genetic tests that would facilitate diagnosis. A better understanding of affected genes and pathways is also necessary for targeting of genes that may improve treatment strategies. To date several susceptibility genes have been reported from genome-wide association studies (GWAS), but little is known about specific variants that affect disease development. Here, we performed quantitative proteomics and whole-genome sequencing (WGS). Quantitative proteomics revealed NLRP2 as the most significantly up-regulated protein in neural stem cells and mature neural cells obtained from BD-patient cell samples. These results are in concordance with our previously published transcriptome analysis. Furthermore, the levels of FEZ2 and CADM2 proteins were also significantly differentially expressed in BD compared to control derived cells. The levels of FEZ2 were significantly downregulated in neural stem cells (NSC) while CADM2 was significantly up-regulated in mature neuronal cell culture. Promising novel candidate mutations were identified in the ANK3, NEK3, NEK7, TUBB, ANKRD1, and BRD2 genes. A literature search of candidate variants and deregulated proteins revealed that there are several connections to microtubule function for the molecules putatively involved. Microtubule function in neurons is critical for axon structure and axonal transport. A functional dynamic microtubule is also needed for an advocate response to cellular and environmental stress. If microtubule dynamics is compromised by mutations, it could be followed by deregulated expression forming a possible explanation for the inherited vulnerability to stressful life events that have been proposed to trigger mood episodes in BD patients.

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Deficits in axon‐associated proteins in prefrontal white matter in bipolar disorder but not schizophrenia

Abstract: These data provide evidence for deficits in axon-associated proteins in prefrontal white matter in BD. Findings are suggestive of decreased axonal density or dysregulation of axonal function in this disorder.

Cited by 19 publications

References 72 publications

Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages

Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages

Disruption of The Psychiatric Risk Gene Ankyrin 3 Enhances Microtubule Dynamics Through GSK3/CRMP2 Signaling

Identification of candidate genetic variants and altered protein expression in neural stem and mature neural cells support altered microtubule function to be an essential component in bipolar disorder

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