Advertisement

Journal of Molecular Neuroscience

, Volume 62, Issue 3–4, pp 304–308 | Cite as

Evidence towards RNA Binding Motif (RNP1, RRM) Protein 3 (RBM3) as a Potential Biomarker of Lithium Response in Bipolar Disorder Patients

  • Eleni Merkouri Papadima
  • Paola Niola
  • Carla Melis
  • Claudia Pisanu
  • Donatella Congiu
  • Cristiana Cruceanu
  • Juan Pablo Lopez
  • Gustavo Turecki
  • Raffaella Ardau
  • Giovanni Severino
  • Caterina Chillotti
  • Maria Del Zompo
  • Alessio SquassinaEmail author
Article

Abstract

Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 × 10−16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner.

Keywords

Circadian rhythm Gene expression Lithium response Neuroprotection Bipolar disorder Mood stabilizers 

Abbreviations

BD

Bipolar disorder

RBM3

RNA binding motif (RNP1, RRM) protein 3

LCLs

Lymphoblastoid cell lines

RT-qPCR

Quantitative reverse transcription polymerase chain reaction

NPCs

Neural progenitor cells

FC

Fold change

R

Excellent responders

NR

Non-responders

CH

Cluster headache

DEGs

Differentially expressed genes

IPSC

Induced pluripotent stem cell

ΔΔCt

Comparative Ct method

FDR

False discovery rate

NO

Nitric oxide

Nr1d1, NR1D1

Nuclear receptor subfamily 1 group D member 1

GSK3β

Glycogen synthase kinase 3 beta

IGF-1

Insulin-like growth factor 1

PBMCs

Peripheral blood mononuclear cells

Notes

Acknowledgements

This work was partially funded by a grant from Regione Autonoma della Sardegna (RAS), L7/2007, 2013, call 2013, grant number: 79506. Moreover, the authors wish to thank the patients and their families for participating in this study.

Compliance with Ethical Standards

Our study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans, was approved by the ethics committee of the Teaching Hospital of Cagliari (Italy), and written informed consent was obtained from all participants.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12031_2017_938_MOESM1_ESM.xlsx (1018 kb)
Online resource 1 Full list of differentially expressed genes with False Discovery Rate (FDR) smaller than 0.05. Microarray data from comparing bipolar disorder patients, responders and non-responders to lithium. (XLSX 1018 kb)

References

  1. Alda M (2015) Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry 20:661–670CrossRefPubMedPubMedCentralGoogle Scholar
  2. APA (2002). Work Group on Bipolar Disorder. Practice guidelines for the treatment of patients with Bipolar Disorder.Second Edition. (American Psychiatric Association Practice Guidelines)Google Scholar
  3. Boivin DB (2000) Influence of sleep-wake and circadian rhythm disturbances in psychiatric disorders. J Psychiatry Neurosci 25:446–458PubMedPubMedCentralGoogle Scholar
  4. Chip S, Zelmer A, Ogunshola OO, Felderhoff-Mueser U, Nitsch C, Bührer C, Wellmann S (2011) The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. Neurobiol Dis 43:388–396CrossRefPubMedGoogle Scholar
  5. Chiu CT, Chuang DM (2010) Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacol Ther 128:281–304CrossRefPubMedPubMedCentralGoogle Scholar
  6. Costa M, Squassina A, Piras IS, Pisanu C, Congiu D, Niola P, Angius A, Chillotti C, Ardau R, Severino G et al (2015) Preliminary transcriptome analysis in lymphoblasts from cluster headache and bipolar disorder patients implicates dysregulation of circadian and serotonergic genes. J Mol Neurosci 56:688–695CrossRefPubMedGoogle Scholar
  7. Cruceanu C, Tan PP, Rogic S, Lopez JP, Torres-Platas SG, Gigek CO, Alda M, Rouleau GA, Pavlidis P, Turecki G (2015) Transcriptome sequencing of the anterior cingulate in bipolar disorder: dysregulation of G protein-coupled receptors. Am J Psychiatry 172:1131–1140CrossRefPubMedGoogle Scholar
  8. da Silva EG, Pfaffenseller B, Walz J, Stertz L, Fries G, Rosa AR, Magalhães PV (2017) Peripheral insulin-like growth factor 1 in bipolar disorder. Psychiatry Res 250:30–34CrossRefPubMedGoogle Scholar
  9. Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoël MJ, Bertrand F, Cherqui G, Perret C, Capeau J (2001) Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene 20:252–259CrossRefPubMedGoogle Scholar
  10. Grof P, Duffy A, Cavazzoni P, Grof E, Garnham J, MacDougall M, O'Donovan C, Alda M (2002) Is response to prophylactic lithium a familial trait? J Clin Psychiatry 63:942–947CrossRefPubMedGoogle Scholar
  11. Gurwitz D (2016) Human iPSC-derived neurons and lymphoblastoid cells for personalized medicine research in neuropsychiatric disorders. Dialogues Clin Neurosci 18:267–276PubMedPubMedCentralGoogle Scholar
  12. Johnson CP, Follmer RL, Oguz I, Warren LA, Christensen GE, Fiedorowicz JG, Magnotta VA, Wemmie JA (2015) Brain abnormalities in bipolar disorder detected by quantitative T1ρ mapping. Mol Psychiatry 20:201–206CrossRefPubMedPubMedCentralGoogle Scholar
  13. Liu Y, Hu W, Murakawa Y, Yin J, Wang G, Landthaler M, Yan J (2013) Cold-induced RNA-binding proteins regulate circadian gene expression by controlling alternative polyadenylation. Sci Rep 3:2054CrossRefPubMedPubMedCentralGoogle Scholar
  14. Manchia M, Lampus S, Chillotti C, Sardu C, Ardau R, Severino G, Del Zompo M (2008) Age at onset in Sardinian bipolar I patients: evidence for three subgroups. Bipolar Disord 10:443–446CrossRefPubMedGoogle Scholar
  15. McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR (2012) Lithium toxicity profile: a systematic review and meta-analysis. Lancet 379:721–728CrossRefPubMedGoogle Scholar
  16. Meffre D, Grenier J, Bernard S, Courtin F, Dudev T, Shackleford G, Jafarian-Tehrani M, Massaad C (2014) Wnt and lithium: a common destiny in the therapy of nervous system pathologies? Cell Mol Life Sci 71:1123–1148CrossRefPubMedGoogle Scholar
  17. Merikangas KR, Akiskal HS, Angst J, Greenberg PE, Hirschfeld RM, Petukhova M, Kessler RC (2007) Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64:543–552CrossRefPubMedPubMedCentralGoogle Scholar
  18. Milanesi E, Hadar A, Maffioletti E, Werner H, Shomron N, Gennarelli M, Schulze TG, Costa M, Del Zompo M, Squassina A et al (2015) Insulin-like growth factor 1 differentially affects lithium sensitivity of Lymphoblastoid cell lines from lithium responder and non-responder bipolar disorder patients. J Mol Neurosci 56:681–687CrossRefPubMedGoogle Scholar
  19. Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB, Faulk MW, Koch S, Glitz DA, Jolkovsky L et al (2000) Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects? Biol Psychiatry 48:1–8CrossRefPubMedGoogle Scholar
  20. Moreira J, Geoffroy PA (2016) Lithium and bipolar disorder: impacts from molecular to behavioural circadian rhythms. Chronobiol Int 33:351–373CrossRefPubMedGoogle Scholar
  21. Neitzel H (1986) A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet 73:320–326CrossRefPubMedGoogle Scholar
  22. Pereira AC, McQuillin A, Puri V, Anjorin A, Bass N, Kandaswamy R, Lawrence J, Curtis D, Sklar P, Purcell SM et al (2011) Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 156:177–187CrossRefPubMedGoogle Scholar
  23. Peretti D, Bastide A, Radford H, Verity N, Molloy C, Martin MG, Moreno JA, Steinert JR, Smith T, Dinsdale D et al (2015) RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature 518:236–239CrossRefPubMedPubMedCentralGoogle Scholar
  24. Pringsheim T (2002) Cluster headache: evidence for a disorder of circadian rhythm and hypothalamic function. Can J Neurol Sci 29:33–40CrossRefPubMedGoogle Scholar
  25. Severino G, Squassina A, Costa M, Pisanu C, Calza S, Alda M, Del Zompo M, Manchia M (2013) Pharmacogenomics of bipolar disorder. Pharmacogenomics 14:655–674CrossRefPubMedGoogle Scholar
  26. Sie L, Loong S, Tan EK (2009) Utility of lymphoblastoid cell lines. J Neurosci Res 87:1953–1959CrossRefPubMedGoogle Scholar
  27. Squassina A, Costa M, Congiu D, Manchia M, Angius A, Deiana V, Ardau R, Chillotti C, Severino G, Calza S et al (2013) Insulin-like growth factor 1 (IGF-1) expression is up-regulated in lymphoblastoid cell lines of lithium responsive bipolar disorder patients. Pharmacol Res 73:1–7CrossRefPubMedGoogle Scholar
  28. Tu KY, Wu MK, Chen YW, Lin PY, Wang HY, Wu CK, Tseng PT (2016) Significantly higher peripheral insulin-like growth factor-1 levels in patients with major depressive disorder or bipolar disorder than in healthy controls: a meta-analysis and review under guideline of PRISMA. Medicine (Baltimore) 95:e2411CrossRefGoogle Scholar
  29. Venugopal A, Subramaniam D, Balmaceda J, Roy B, Dixon DA, Umar S, Weir SJ, Anant S (2016) RNA binding protein RBM3 increases β-catenin signaling to increase stem cell characteristics in colorectal cancer cells. Mol Carcinog 55:1503–1516CrossRefPubMedGoogle Scholar
  30. Yang HJ, Ju F, Guo XX, Ma SP, Wang L, Cheng BF, Zhuang RJ, Zhang BB, Shi X, Feng ZW et al (2017) RNA-binding protein RBM3 prevents NO-induced apoptosis in human neuroblastoma cells by modulating p38 signaling and miR-143. Sci Rep 7:41738CrossRefPubMedPubMedCentralGoogle Scholar
  31. Yildiz A, Vieta E, Leucht S, Baldessarini RJ (2011) Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology 36:375–389CrossRefPubMedGoogle Scholar
  32. Yin L, Wang J, Klein PS, Lazar MA (2006) Nuclear receptor rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science 311:1002–1005CrossRefPubMedGoogle Scholar
  33. Zhu X, Zelmer A, Kapfhammer JP, Wellmann S (2016) Cold-inducible RBM3 inhibits PERK phosphorylation through cooperation with NF90 to protect cells from endoplasmic reticulum stress. FASEB J 30:624–634CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Eleni Merkouri Papadima
    • 1
  • Paola Niola
    • 1
  • Carla Melis
    • 1
  • Claudia Pisanu
    • 1
  • Donatella Congiu
    • 1
  • Cristiana Cruceanu
    • 2
  • Juan Pablo Lopez
    • 2
  • Gustavo Turecki
    • 2
  • Raffaella Ardau
    • 3
  • Giovanni Severino
    • 1
  • Caterina Chillotti
    • 3
  • Maria Del Zompo
    • 1
    • 3
  • Alessio Squassina
    • 1
    Email author
  1. 1.Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, School of MedicineUniversity of CagliariCagliariItaly
  2. 2.McGill Group for Suicide Studies, Douglas Mental Health University InstituteMcGill UniversityMontrealCanada
  3. 3.Unit of Clinical Pharmacology of the University Hospital of CagliariCagliariItaly

Personalised recommendations