Distinct Patterns of Cell Adhesion, Migration, and Morphology in Olfactory Neuroepithelium Cells of Bipolar Disorder Patients

Overview

Journal Mol Med

Publisher Biomed Central

Specialties General Medicine
Molecular Biology

Date 2024 Dec 23

PMID 39716063

Authors

Alejandra Delgado-Sequera

Jose I Perez-Revuelta

Andres Caballero-Garcia

MACarmen Duran-Ruiz

Cristina Romero-Lopez-Alberca

Clara Garcia-Mompo

Francisco Gonzalez-Saiz

Manuel Rodriguez-Iglesias

Daniel Sanchez-Morillo

Patricia Robledo

Victor Perez

Esther Berrocoso

Maria Hidalgo-Figueroa

Affiliations

Soon will be listed here.

Abstract

Background: Bipolar disorder (BD) is a severe, chronic mental illness that remains difficult to diagnose due to the lack of specific biomarkers, relying primarily on clinical assessments. Early diagnosis and treatment are essential for improving prognosis and lowering suicide risk. This study aimed to identify biomarkers and therapeutic targets by utilizing olfactory neuroepithelium (ONE) cells from patients with BD and controls.

Methods: Immunofluorescence of ONE cells, along with proteomic and RNA sequencing analyses, was performed to investigate cytoskeletal changes and pathways involved in cell adhesion, movement, and morphology. Additionally, potential biomarkers were investigated in blood samples to improve clinical accessibility.

Results: Thus, according to functional assays, ONE cells derived from BD patients exhibited decreased substrate adhesion, reduced cell migration, and morphological changes compared to control cells. In addition, proteomic and RNAseq analyses in ONE cells and peripheral blood mononuclear cells (PBMCs) revealed alterations in pathways such as RhoA/PAK/Integrin and Actin Cytoskeleton Signaling, as well as significant changes in inflammatory and immunological pathways. AUROC analysis identified proteins like PTK2 as potential diagnostic biomarkers, showing altered expression in both ONE cells and PBMCs. PTK2 RNA expression correlated with distinct morphological traits in BD ONE cells.

Conclusions: In summary, this study identified cytoskeletal alterations, reduced adhesion, and disrupted migration patterns in BD ONE cells, highlighting molecular mechanisms underlying these changes and emphasizing PTK2's role as a potential diagnostic biomarker for BD.

References

Garcia-Gutierrez M, Navarrete F, Sala F, Gasparyan A, Austrich-Olivares A, Manzanares J . Biomarkers in Psychiatry: Concept, Definition, Types and Relevance to the Clinical Reality. Front Psychiatry. 2020; 11:432. PMC: 7243207. DOI: 10.3389/fpsyt.2020.00432. View

Zhao Z, Xu J, Chen J, Kim S, Reimers M, Bacanu S . Transcriptome sequencing and genome-wide association analyses reveal lysosomal function and actin cytoskeleton remodeling in schizophrenia and bipolar disorder. Mol Psychiatry. 2014; 20(5):563-572. PMC: 4326626. DOI: 10.1038/mp.2014.82. View

Gonda X, Pompili M, Serafini G, Montebovi F, Campi S, Dome P . Suicidal behavior in bipolar disorder: epidemiology, characteristics and major risk factors. J Affect Disord. 2012; 143(1-3):16-26. DOI: 10.1016/j.jad.2012.04.041. View

Crawford J, Hoeflich K, Rudolph J . p21-Activated kinase inhibitors: a patent review. Expert Opin Ther Pat. 2012; 22(3):293-310. DOI: 10.1517/13543776.2012.668758. View

Delgado-Sequera A, Hidalgo-Figueroa M, Barrera-Conde M, Duran-Ruiz M, Castro C, Fernandez-Aviles C . Olfactory Neuroepithelium Cells from Cannabis Users Display Alterations to the Cytoskeleton and to Markers of Adhesion, Proliferation and Apoptosis. Mol Neurobiol. 2020; 58(4):1695-1710. DOI: 10.1007/s12035-020-02205-9. View

Vieta E, Berk M, Schulze T, Carvalho A, Suppes T, Calabrese J . Bipolar disorders. Nat Rev Dis Primers. 2018; 4:18008. DOI: 10.1038/nrdp.2018.8. View

Armendariz B, Masdeu M, Soriano E, Urena J, Burgaya F . The diverse roles and multiple forms of focal adhesion kinase in brain. Eur J Neurosci. 2014; 40(11):3573-90. DOI: 10.1111/ejn.12737. View

Leza J, Garcia-Bueno B, Bioque M, Arango C, Parellada M, Do K . Inflammation in schizophrenia: A question of balance. Neurosci Biobehav Rev. 2015; 55:612-26. DOI: 10.1016/j.neubiorev.2015.05.014. View

Barnett J, Smoller J . The genetics of bipolar disorder. Neuroscience. 2009; 164(1):331-43. PMC: 3637882. DOI: 10.1016/j.neuroscience.2009.03.080. View

10.

Benitez-King G, Valdes-Tovar M, Trueta C, Galvan-Arrieta T, Argueta J, Alarcon S . The microtubular cytoskeleton of olfactory neurons derived from patients with schizophrenia or with bipolar disorder: Implications for biomarker characterization, neuronal physiology and pharmacological screening. Mol Cell Neurosci. 2016; 73:84-95. DOI: 10.1016/j.mcn.2016.01.013. View

11.

ODushlaine C, Kenny E, Heron E, Donohoe G, Gill M, Morris D . Molecular pathways involved in neuronal cell adhesion and membrane scaffolding contribute to schizophrenia and bipolar disorder susceptibility. Mol Psychiatry. 2010; 16(3):286-92. DOI: 10.1038/mp.2010.7. View

12.

Mertens J, Wang Q, Kim Y, Yu D, Pham S, Yang B . Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015; 527(7576):95-9. PMC: 4742055. DOI: 10.1038/nature15526. View

13.

Unterholzner J, Millischer V, Wotawa C, Sawa A, Lanzenberger R . Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders. Int J Neuropsychopharmacol. 2021; 24(10):759-775. PMC: 8538891. DOI: 10.1093/ijnp/pyab037. View

14.

Delgado-Sequera A, Garcia-Mompo C, Gonzalez-Pinto A, Hidalgo-Figueroa M, Berrocoso E . A Systematic Review of the Molecular and Cellular Alterations Induced by Cannabis That May Serve as Risk Factors for Bipolar Disorder. Int J Neuropsychopharmacol. 2024; 27(2). PMC: 10863486. DOI: 10.1093/ijnp/pyae002. View

15.

Cui Y, Rolova T, Fagerholm S . The role of integrins in brain health and neurodegenerative diseases. Eur J Cell Biol. 2024; 103(3):151441. DOI: 10.1016/j.ejcb.2024.151441. View

16.

Galindo L, Moreno E, Lopez-Armenta F, Guinart D, Cuenca-Royo A, Izquierdo-Serra M . Cannabis Users Show Enhanced Expression of CB-5HT Receptor Heteromers in Olfactory Neuroepithelium Cells. Mol Neurobiol. 2018; 55(8):6347-6361. DOI: 10.1007/s12035-017-0833-7. View

17.

Gigase F, Snijders G, Boks M, de Witte L . Neurons and glial cells in bipolar disorder: A systematic review of postmortem brain studies of cell number and size. Neurosci Biobehav Rev. 2019; 103:150-162. DOI: 10.1016/j.neubiorev.2019.05.027. View

18.

Solis-Chagoyan H, Calixto E, Figueroa A, Montano L, Berlanga C, Rodriguez-Verdugo M . Microtubule organization and L-type voltage-activated calcium current in olfactory neuronal cells obtained from patients with schizophrenia and bipolar disorder. Schizophr Res. 2013; 143(2-3):384-9. DOI: 10.1016/j.schres.2012.11.035. View

19.

Fraser C, Berry K, Hershey J, Doudna J . eIF3j is located in the decoding center of the human 40S ribosomal subunit. Mol Cell. 2007; 26(6):811-9. DOI: 10.1016/j.molcel.2007.05.019. View

20.

Kermath B, Vanderplow A, Cahill M . Dysregulated Prefrontal Cortical RhoA Signal Transduction in Bipolar Disorder with Psychosis: New Implications for Disease Pathophysiology. Cereb Cortex. 2019; 30(1):59-71. DOI: 10.1093/cercor/bhz070. View