Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by HILLEMACHER, T. Articles by BLEICH, S. Search for Related Content PubMed Citation Articles by HILLEMACHER, T. Articles by BLEICH, S. Depression Genetics

Homocysteine and Epigenetic DNA Methylation: A Biological Model for Depression?

To The Editor: In the article by Marshal Folstein, M.D., et al. (1), published in the June 2007 issue of the Journal, the authors described the homocysteine hypothesis of depression. This study provides a fundamental overview of the current knowledge regarding involvement of the homocysteine metabolism in the pathogenesis of depressive disorders.

Dr. Folstein et al. hypothesized that hyperhomocysteinemia may lead to an elevated risk of depression, mainly via acting as a cerebrovascular risk factor and by causing neurotransmitter deficiency. However, another important pathophysiological mechanism should be taken into account when discussing the homocysteine hypothesis of depression. Homocysteine is metabolized to methionine after activation to S-adenosyl-methionine, which is known to act as a methyldonator. Furthermore, homocysteine itself influences global and gene promoter-specific deoxyribonucleic acid (DNA) methylation (2). Acute homocysteine treatment has been shown to cause misregulation of different gene-specific promoters and changes of corresponding messenger ribonucleic acid (mRNA) levels (3). There is growing evidence that altered promoter-DNA methylation permits genome plasticity and adaption to a variety of environmental factors. This may provide the molecular base for a dynamic interaction between the environment and gene expression, regulated by modified promoter methylation. It has been suggested that these molecular mechanisms play a substantial role in the pathogenesis of different psychiatric disorders associated with hyperhomocysteinemia (4), including schizophrenia, eating disorders, and addiction (2, 5, 6). These epigenetic alterations may directly influence monoaminergic neurotransmission by modifying promoter methylation of candidate genes such as COMT and 5-HTTLPR (6, 7). Dysregulation of epigenetic-DNA methylation may therefore be one important element when discussing the homocysteine hypothesis of depression.

Footnotes

The authors report no competing interests.

This letter (doi: 10.1176/appi.ajp.2007.07060881) was accepted for publication in July 2007.

References

1. Folstein M, Liu T, Peter I, Buel J, Arsenault L, Scott T, Qiu WW: The homocysteine hypothesis of depression. Am J Psychiatry 2007; 164:861–867[Abstract/Free Full Text]
2. Bleich S, Lenz B, Ziegenbein M, Beutler S, Frieling H, Kornhuber J, Bönsch D: Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcohol Clin Exp Res 2006; 30:587–591[CrossRef][Medline]
3. Lenz B, Bleich S, Beutler S, Schlierf B, Schwager K, Reulbach U, Kornhuber J, Bönsch D: Homocysteine regulates expression of HERP by DNA methylation involving the AARE and CREB binding sites. Exp Cell Res 2006; 312:4049–4055[CrossRef][Medline]
4. Tsankova N, Renthal W, Kumar A, Nestler EJ: Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 2007; 8:355–367[CrossRef][Medline]
5. Frieling H, Gozner A, Römer KD, Lenz B, Bönsch D, Wilhelm J, Hillemacher T, de Zwaan M, Kornhuber J, Bleich S: Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa. Mol Psychiatry 2007; 12:229–230[CrossRef][Medline]
6. Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J, Pan H, Papageorgis P, Ponte JF, Sivaraman V, Tsuang MT, Thiagalingam S: Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 2006; 15:3132–3145[Abstract/Free Full Text]
7. Mill J, Petronis A: Molecular studies of major depressive disorder: the epigenetic perspective. Mol Psychiatry 2007; 12:799–814[CrossRef][Medline]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by HILLEMACHER, T. Articles by BLEICH, S. Search for Related Content PubMed Citation Articles by HILLEMACHER, T. Articles by BLEICH, S. Depression Genetics

Get information about faster international access.

Privacy Policy

Copyright © 2007 American Psychiatric Association. All rights reserved.

Home | Search | Current Issue | Past Issues | Subscribe | All APPI Journals | Help | Contact Us