Korkut ULUCAN, MESUT KARAHAN, ESRA SAĞLAM

Folik asit metabolizmasının biyokimyasal ve moleküler açıdan Parkinson, Alzheimer, bipolar ve şizofrenik bozukluklara etkisi

Folatlar, hücre metabolizması için büyük öneme sahip B vitamini türevleridir. Hücrelerde bölünme, büyüme, amino asit ve pürin bazlarının biyosentezinde görev alırlar. Metilentetrahidrofolat redüktaz enzimi folatların metabolizma- sında önemlidir ve bu enzimi kodlayan gendeki bazı varyasyonlar, genin kodladığı enzimin çalışma hızına etki ederek hücrelerde sorunlara neden olabilirler. Eksiklikleri noral tüp defektleri gibi embriyonel sorunlardan konje- nital anomalilere kadar geniş yelpazede patolojilerin oluşmasına neden olabilir. Son yıllarda metilentetrahidrofolat redüktaz genindeki varyasyonlar ile Parkinson, Alzheimer, bipolar ve şizofrenik bozukluklar gibi nörolojik ve psiki- yatrik hastalıklar arasında ilişkiler kurulmuş ve bu varyasyonarın bazı hastalıkların oluşumundaki önemleri ortaya çıkarılmıştır. Bu derlememizde folik asit hakkında kısa bir bilgi verildikten sonra folik asidin ve metabolizmasında görev alan metilentetrahidrofolat geninin Parkinson, Alzheimer, bipolar ve şizofrenik bozukluklarla ilişkisinin önemini belirtmeyi amaçladık.

Biochemical and molecular effects of folic acid metabolism to Parkinson, Alzheimer, bipolar and schizophrenic diseases

Folates are the vitamin B derivatives that play important roles on cell metabolism. They function in cell prolife- ration, cell growth, amino acid and purine biosynthesis. Methylenetetrahydrofolate reductase enzyme is crucial for folate metabolism and some variations in the gene that encode the enzyme may cause some problems affecting enzyme kinetics. Absence of folates causes a range of pathologies from neural tube defects to congenital ano- malies. Recently, variations in the methylenetetrahydrofolate reductase gene are associated with neurological and psychiatric diseases like Parkinson‟s, Alzheimer‟s and bipolar diseases and the role of these variations in these diseases were better diagnosed and described. In this review, upon giving brief information about folates, we aim to specify the association of methylenetetrahydrofolate reductase gene with Parkinson‟s, Alzheimer‟s, bipolar and schizophrenic diseases.

PDF

___

1. Miller AL. The methylation, neurotransmitter, and antioxidant connections between folate and dep- ression. Altern Med Rev 2008; 13:216-226.
2. Wisniewska K, Wysocki J. The importance of folic acid in the primary prevention of congenital malformations. Arch Perinatal Med 2008; 14:32-40.
3. Czeizel AE, Dudas I. Prevention of the first ocur- rence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 1992; 327:1832-1835.
4. Botto LD, Olney RS, Erickson JD. Vitamin supplements and the risk for congenital anoma- lies other than neural tube defects. AmJ Med Genet Part C 2004;125C:12-21.
5. Ziemlański Ś, Wartanowicz M. Rola folianów w żywieniu kobiet i dzieci. Pediatr. Współcz. Gas- troenterol Hepatol Żyw Dziec 2001; 3:119-125.
6. Kunachowicz H, Nadolna I, Stoś K. Produkty wzbogacane w kwas foliowy i ich rola w promocji zdrowia. Przegl Lek 2001; 61:30-34.
7. Mierzecki A, Bukowska H, Krzystolik A. Kwas foliowy. Co lekarz rodzinny wiedzieć powinien. Lek Rodz 2006; 11:1292-1295.
8. Czeizel AE. The primary prevention of birth defects: Multivitamins or folic acid? Int J Med Sci 2004; 1:50-61.
9. Homberger G, Linnebank M, Winter C. Genomic structure and transcript variants of the human methylenetetrahydrofolate reductase gene. Eur J Hum Genet 2000; 8:725-729.
10. Bailey LB, Duhaney RL, Maneval DR. Vitamin B- 12 status is inversely associated with plasma homocysteine in young women with C677T and/ or A1298C methylenetetrahydrofolate reductase polymorphisms. J Nutr 2002; 132:24665-24709.
11. Kim Y. Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: A para- digm of gene-nutrient interactions in carcino- genesis. Nutr Rev 2000; 58:205-217.
12. Dikmen M. Molecular biology of Methylenetetra- hydrofolate Reductase (MTHFR) enzyme and ıts association with diseases. The Medical Journal of Kocatepe 2004; 5:9-16.
13. Gilbody S, Lewis S, Lightfoot T. Methylenetetra- hydrofolate Reductase (MTHFR) Genetic Poly- morphisms and Psychiatric Disorders: A HuGE Review. Am J Epidemiol 2007; 165:1-13.
14. Murakami K, Mizoue T, Sasaki S, Ohta M, Sato M, Matsushita Y, et al. Dietary intake of folate, other B vitamins, and omega-3 polyunsaturated fatty acids in relation to depressive symptoms in Japanese adults. Nutrition 2008; 24:140-147.
15. Mansoori N, Tripathi M, Luthra K, Alam R, Lakshmy R, Sharma S, et al. MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer's and vascular dementia and their epistatic interaction. Neurobiol Aging 2012; 33:845-1020.
16. Papakostas GI, Petersen T, Lebowitz BD, Mis- choulon D, Ryan JL, Nierenberg AA, et al. The relationship between serum folate, vitamin B12, and homocysteine levels in major depressive dis- order and the timing of improvement with fluoxe- tine. Int J Neuropsychopharmacol 2005; 8:523-528.
17. Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vit- amin B12. J Psychopharmacol 2005; 19:59-65.
18. Bottiglieri T. Homocysteine and folate metab- olism in depression. Prog Neuropsychophar- macol Biol Psychiatry 2005; 29:1103-1112.
19. Hua Y, Zhao H, Kong Y, Ye M. Association be- tween the MTHFR gene and Alzheimer's dis- ease: a meta-analysis. Int J Neurosci 2011; 121:462-741.
20. Zhang MY, Miao L, Li YS, Hu GY. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzhei- mer's disease. Neurosci Res 2010; 68:142-150.
21. Ellingrod VL, Taylor SF, Dalack G, Grove TB, Bly MJ, Brook RD, et al. Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics. J Clin Psychopharma- col 2012; 32:261-265.
22. Rai V. Evaluation of methylenetetrahydrofolate reductase gene variant (C677T) as risk factor for bipolar disorder. 2011; 27; 57:558-1566.
23. Cohen-Woods S, Craig I, Gaysina D, Gray J, Gunasinghe C, Craddock N, et al. The Bipolar Association Case-Control Study (BACCS) and meta-analysis: No association with the 5,10 Methylenetetrahydrofolate reductase gene and bipolar disorder. Am J Med Genet B Neuro- psychiatr Genet 2010; 153B(7):1298-1304.
24. Białecka M, Kurzawski M, Roszmann A, Ro- bowski P, Sitek EJ, Honczarenko K, et al. Asso- ciation of COMT, MTHFR, and SLC19A1 (RFC- 1) polymorphisms with homocysteine blood levels and cognitive impairment in Parkinson's disease. Pharmacogenet Genomics 2012; 22:716-724.
25. Gorgone G, Currò M, Ferlazzo N, Parisi G, Par- netti L, Belcastro V, et al. Coenzyme Q10, hyper- homocysteinemia and MTHFR C677T polymor- phism in levodopa-treated Parkinson's disease patients. Neuromolecular Med 2012; 14:84-90.
26. Fong CS, Shyu HY, Shieh JC, Fu YP, Chin TY, Wang HW, et al. Association of MTHFR, MTR, and MTRR polymorphisms with Parkinson's dis- ease among ethnic Chinese in Taiwan. Clin Chim Acta 2011; 12:332-338.
27. Lin JJ, Yueh KC, Liu CS, Liu JT, Lin SZ. 5,10- methylenetetrahydrofolate reductase C677T gene polymorphism can influence age at onset of Parkinson's disease. Acta Neurol Taiwan 2007; 16:150-157.