Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways

Molecular Psychiatry volume 15, pages 702–711 (2010)Cite this article

Abstract

In our biomarker identification efforts, we have reported earlier on a protein that differs in its electrophoretic mobility between mouse lines bred either for high or low trait anxiety. The altered electrophoretic behavior of enolase phosphatase (EP) is now identified to be caused by two single-nucleotide polymorphisms. In both cases, the genetic polymorphism introduces an amino acid change in the protein's sequence resulting in differential mobility on SDS gels. This was shown by recombinantly expressing the two EP isoforms. Functional studies indicate that the EP isoform from the high anxiety mouse line has a lower enzymatic activity than does its low anxiety mouse counterpart. EP is a member of the methionine salvage pathway that is responsible for the synthesis of S-adenosyl-L-methionine, a natural compound with potential antidepressant activities. In addition, it is linked to the polyamine pathway whose members have functions in anxiety/depression-related behaviors. In a freely-segregating F2 panel, both single-nucleotide polymorphisms were significantly associated with locomotion-independent trait anxiety, further supporting a functional role of EP for this phenotype. The study shows that proteomic analysis can reveal genotypic differences relevant for the phenotype. The identified protein alterations, in turn, can expose metabolic pathways pertinent to the behavioral phenotype.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Hyman SE . Can neuroscience be integrated into DSM-V? Nat Rev Neurosci 2007; 8: 725–731.

    Article  CAS  PubMed  Google Scholar 

  2. Krömer SA, Keßler MS, Milfay D, Birg IN, Bunck M, Czibere L et al. Identification of glyoxalase-I as a protein marker in a mouse model of extremes in trait anxiety. J Neurosci 2005; 25: 4375–4384.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ditzen C, Jastorff AM, Keßler MS, Bunck M, Teplytska L, Erhardt A et al. Protein biomarkers in a mouse model of extremes in trait anxiety. Mol Cell Proteomics 2006; 5: 1914–1920.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang Y, Heinsen MH, Kostic M, Pagani GM, Riera TV, Perovic I et al. Analogs of 1-phosphonooxy-2,2-dihydroxy-3-oxo-5-(methylthio)pentane, an acyclic intermediate in the methionine salvage pathway: a new preparation and characterization of activity with E1 enolase/phosphatase from Klebsiella oxytoca. Biorg Med Chem 2004; 12: 3847–3855.

    Article  CAS  Google Scholar 

  5. Hockl PF, Thyssen SM, Libertun C . An improved HPLC method for identification and quantitation of polyamines and related compounds as benzoylated derivatives. J Liq Chrom Rel Technol 2000; 23: 693–703.

    Article  CAS  Google Scholar 

  6. Keßler MS, Murgatroyd C, Bunck M, Czibere L, Frank E, Jacob J et al. Diabetes insipidus and, partially, low anxiety-related behavior are linked to a SNP-associated vasopressin deficit in LAB mice. Eur J Neurosci 2007; 26: 2857–2864.

    Article  PubMed  Google Scholar 

  7. Bernstein HG, Müller M . The cellular localization of the L-ornithine decarboxylase/polyamine system in normal and diseased central nervous systems. Prog Neurobiol 1999; 57: 485–505.

    Article  CAS  PubMed  Google Scholar 

  8. Pegg AE, Williams-Ashman HG . Stimulation of the decarboxylation of S-adenosylmethionine by putrescine in mammalian tissues. Biochem Biophys Res Comm 1968; 30: 76–82.

    Article  CAS  PubMed  Google Scholar 

  9. Bressa GM . S-adenosyl-l-methionine (SAMe) as antidepressant: Meta-analysis of clinical studies. Acta Neurol Scand Suppl 1994; 154: 7–14.

    Article  CAS  PubMed  Google Scholar 

  10. Silveri MM, Parow AM, Villafuerte RA, Damico KE, Goren J, Stoll AL et al. S-adenosyl-L-methionine: effects on brain bioenergetic status and transverse relaxation time in healthy subjects. Biol Psychiatry 2003; 54: 833–839.

    Article  CAS  PubMed  Google Scholar 

  11. Mill J, Petronis A . Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry 2007; 12: 799–814.

    Article  CAS  PubMed  Google Scholar 

  12. Bottiglieri T . S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr 2002; 76: 1151S–1157S.

    Article  CAS  PubMed  Google Scholar 

  13. Fernández JA, Rojo L, Kuljis RO, Maccioni RB . The damage signals hypothesis of Alzheimer's disease pathogenesis. J Alzheimers Dis 2008; 14: 329–333.

    Article  PubMed  Google Scholar 

  14. Gu F, Zhu M, Shi J, Hu Y, Zhao Z . Enhanced oxidative stress is an early event during development of Alzheimer-like pathologies in presenilin conditional knock-out mice. Neurosci Lett 2008; 440: 44–48.

    Article  CAS  PubMed  Google Scholar 

  15. Yang JL, Weissman L, Bohr VA, Mattson MP . Mitochondrial DNA damage and repair in neurodegenerative disorders. DNA Repair (Amst) 2008; 7: 1110–1120.

    Article  CAS  Google Scholar 

  16. Koene S, Kozicz TL, Rodenburg RJ, Verhaak CM, de Vries MC, Wortmann S et al. Major depression in adolescent children consecutively diagnosed with mitochondrial disorder. J Affect Disord 2008; e-pub ahead of print.

  17. Michel TM, Camara S, Tatschner T, Frangou S, Sheldrick AJ, Riederer P et al. Increased xanthine oxidase in the thalamus and putamen in depression. World J Biol Psychiatry 2008; 12: 1–7.

    Article  Google Scholar 

  18. Rammal H, Bouayed J, Younos C, Soulimani R . The impact of high anxiety level on the oxidative status of mouse peripheral blood lymphocytes, granulocytes and monocytes. Eur J Pharmacol 2008; 589: 173–175.

    Article  CAS  PubMed  Google Scholar 

  19. Ordonez LA, Wurtman RJ . Folic acid deficiency and methyl group metabolism in rat brain: effects of L-dopa. Arch Biochem Biophys 1974; 160: 372–376.

    Article  CAS  PubMed  Google Scholar 

  20. Carney MW . Serum folate values in 423 psychiatric patients. Br Med J 1967; 4: 512–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Thornton WE, Thornton BP . Folic acid, mental function, and dietary habits. J Clin Psychiatry 1978; 39: 315–319, 322.

    CAS  PubMed  Google Scholar 

  22. Carney MW, Sheffield BF . Associations of subnormal serum folate and vitamin B12 values and effects of replacement therapy. J Nerv Ment Dis 1970; 150: 404–412.

    Article  CAS  PubMed  Google Scholar 

  23. Genedani S, Saltini S, Benelli A, Filaferro M, Bertolini A . Influence of SAMe on the modifications of brain polyamine levels in an animal model of depression. Neuroreport 2001; 12: 3939–3942.

    Article  CAS  PubMed  Google Scholar 

  24. Sequeira A, Gwadry FG, Ffrench-Mullen JM, Canetti L, Gingras Y, Casero Jr RA et al. Implication of SSAT by gene expression and genetic variation in suicide and major depression. Arch Gen Psychiatry 2006; 63: 35–48.

    Article  CAS  PubMed  Google Scholar 

  25. Gilad GM, Gilad VH, Casanova MF, Casero Jr RA . Polyamines and their metabolizing enzymes in human frontal cortex and hippocampus: preliminary measurements in affective disorders. Biol Psychiatry 1995; 38: 227–234.

    Article  CAS  PubMed  Google Scholar 

  26. Fiori LM, Turecki G . Implication of the polyamine system in mental disorders. J Psychiatry Neurosci 2008; 33: 102–110.

    PubMed  PubMed Central  Google Scholar 

  27. Williams K . Interaction of polyamines with ion channels. Biochem J 1997; 325: 289–297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Johnson TD . Modulation of channel function by polyamines. Trends Pharmacol Sci 1996; 17: 22–27.

    Article  CAS  PubMed  Google Scholar 

  29. Skolnik P . Antidepressants for the new millenium. Eur J Pharmacol 1999; 375: 31–40.

    Article  Google Scholar 

  30. Levine J, Cole DP, Chengappa KN, Gershon S . Anxiety disorders and major depression, together or apart. Depress Anxiety 2001; 14: 94–104.

    Article  CAS  PubMed  Google Scholar 

  31. Landgraf R, Keßler M, Bunck M, Murgatroyd C, Spengler D, Zimbelmann M et al. Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: focus on vasopressin and glyoxalase-I. Neurosci Biobehav Rev 2007; 31: 89–102.

    Article  CAS  PubMed  Google Scholar 

  32. Fernandez-Teruel A, Escorihuela RM, Gray JA, Aguilar R, Gil L, Gimenez-Llort L et al. A quantitative trait locus influencing anxiety in the laboratory rat. Genome Res 2002; 12: 618–626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Henderson ND, Turri MG, DeFries JC, Flint J . QTL analysis of multiple behavioral measures of anxiety in mice. Behav Genet 2004; 34: 267–293.

    Article  PubMed  Google Scholar 

  34. Turri MG, DeFries JC, Henderson ND, Flint J . Multivariate analysis of quantitative trait loci influencing variation in anxiety-related behavior in laboratory mice. Mamm Genome 2004; 15: 69–76.

    Article  PubMed  Google Scholar 

  35. Baum AE, Solberg LC, Churchill GA, Ahmadiyeh N, Takahashi JS, Redei EE . Test- and behavior-specific genetic factors affect WKY hypoactivity in tests of emotionality. Behav Brain Res 2006; 169: 220–230.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by a BMBF QuantPro grant and by the Max Planck Society.

Author information

Author notes

  1. C Ditzen, J Varadarajulu and L Czibere: These authors contributed equally to this work.

Authors and Affiliations

  1. Max Planck Institute of Psychiatry, Munich, Germany

    C Ditzen, J Varadarajulu, L Czibere, M Gonik, B S Targosz, B Hambsch, T Bettecken, M S Keßler, E Frank, M Bunck, L Teplytska, A Erhardt, F Holsboer, B Müller-Myhsok, R Landgraf & C W Turck

Authors
  1. C Ditzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Varadarajulu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Czibere
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Gonik
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B S Targosz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Hambsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Bettecken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M S Keßler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Bunck
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Teplytska
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A Erhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. F Holsboer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. B Müller-Myhsok
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R Landgraf
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. C W Turck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C W Turck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ditzen, C., Varadarajulu, J., Czibere, L. et al. Proteomic-based genotyping in a mouse model of trait anxiety exposes disease-relevant pathways. Mol Psychiatry 15, 702–711 (2010). https://doi.org/10.1038/mp.2008.146

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.146

Keywords

This article is cited by

Search

Advanced search

Quick links