SIRT1 Gen Polimorfizmleri ve Parkinson Hastalığı Arasındaki İlişkinin Araştırılması

Yıl 2020, Cilt: 25 Sayı: 3, 230 - 236, 29.10.2020

Meryem Kuşçu , Esra Aciman Demirel , Esra Ermiş , Sevim Karakaş Çelik

https://doi.org/10.21673/anadoluklin.702828

Öz

Amaç: Parkinson hastalığı, beyinde substansiya nigrada yoğunlaşmış dopaminerjik nöronların kaybı nedeniyle yeterince dopamin üretilememesi sonucu ortaya çıkan bir hastalıktır. Oksidatif stres ve mitokondriyal disfonksiyon patogenezde merkezî bir rol oynar. Hücreleri oksidatif strese karşı koruduğu tespit edilen Sirtuin1 (SIRT1) geni Parkinson hastalığına yatkınlıkla ilişkilendirilmiştir. Bu çalışmada SIRT1 geni rs7895833 ve rs2273773 polimorfizmleri ile Parkinson hastalığı arasındaki ilişkiyi araştırmak amaçlanmıştır.

Gereç ve Yöntemler: Çalışmamız 40 Parkinson hastası (hasta grubu) ile 50 sağlıklı birey (kontrol grubu) içerdi. rs7895833 polimorfizmi için polimeraz zincir reaksiyonu–confronting two-pair primers (PCR-CTPP) yöntemi, rs2273773 polimorfizmi içinse polimeraz zincir reaksiyonu–restriksiyon parça uzunluk polimorfizmi (PCR-RFLP) yöntemi kullanıldı.

Bulgular: rs7895833 polimorfizmi için sırasıyla hasta ve kontrol gruplarındaki genotip dağılımı AA (%62,5–%53,1), AG (%27,5–%40,8), GG (%10,0–%6,1) şeklindeydi. rs2273773 polimorfizmi için ise hasta ve kontrol grubu genotip frekansları şu şekildeydi: TT (%90,0–%98,0), CT (%10,0–%2,0). rs2273773 ve rs7895833 polimorfizmleri bakımından hasta ve kontrol grupları arasında istatistiksel olarak anlamlı bir fark tespit edilmedi (p>0,05).

Tartışma ve Sonuç: Bulgularımız incelenen SIRT1 gen polimorfizmlerinin Parkinson hastalığı gelişiminde zemin hazırlayıcı bir rol oynamadığına işaret etmektedir.

Anahtar Kelimeler

Parkinson hastalığı, Sirtuin 1, polimorfizm, oksidatif stres, SIRT1

Destekleyen Kurum

TÜBİTAK

Proje Numarası

1919B011600036

An Investigation of the Relationship between SIRT1 Gene Polymorphisms and Parkinson’s Disease

Öz

Aim: Parkinson’s disease is a disorder caused by insufficient dopamin production due to the loss of dopaminergic neurons concentrated in the substantia nigra of the brain. Oxidative stress and mitochondrial dysfunction play a central role in the pathogenesis. The Sirtuin1 (SIRT1) gene, shown to protect cells against oxidative stress, has been reported to be associated with predisposition to Parkinson’s disease. In this study, we aimed to investigate the relationship between Parkinson’s disease and the SIRT1 gene polymorphisms rs7895833 and rs2273773.

Materials and Methods: The study included 40 patients with Parkinson’s disease (the patient group) and 50 healthy individuals (the control group). The polymerase chain reaction with confronting two-pair primers (PCR-CTPP) and polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) methods were used for the rs7895833 and rs2273773 polymorphisms, respectively.

Results: For the rs7895833 polymorphism, the genotype distribution for the patient and control groups respectively was as follows: AA (62.5%–53.1%), AG (27.5%–40.8%), GG (10.0%–6.1%). For the rs2273773 polymorphism, the genotype frequencies for the patient and control groups were as follows: TT (90.0%–98.0%), CT (10.0%–2.0%). No statistically significant difference was found between the patient and control groups in terms of rs2273773 and rs7895833 polymorphisms (p>0.05).

Discussion and Conclusion: Our findings indicated that the SIRT1 gene polymorphisms investigated did not play a predisposing role in the development of Parkinson’s disease.

Anahtar Kelimeler

Parkinson disease, Sirtuin 1, polymorphism, oxidative stress, SIRT1

Proje Numarası

1919B011600036

Kaynakça

• 1. Braak H, Tredici KD. Invited article: nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70:1916–25.
• 2. Devine MJ, Gwinn K, Singleton A, Hardy J. Parkinson’s disease and asynuclein expression. Mov Disord. 2011;26:2160–8.
• 3. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transciptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800.
• 4. Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, ve ark. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci U S A. 2000;97:5807–11.
• 5. Smith JS, Brachmann CB, Celic I, Kenna MA, Muhammad S, Starai VJ, ve ark. A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc Natl Acad Sci U S A. 2000;97:6658–63.
• 6. Nakagawa T, Guarente L. Sirtuins at a glance. J Cell Sci. 2011;124:833–8.
• 7. Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133–71.
• 8. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, ve ark. Negative control of p53 by Sir2 alpha promotes cell survival under stress. Cell. 2001;137:137–48.
• 9. Maiese K, Chong ZZ, Shang YC. OutFOXOing disease and disability: the therapeutic potential of targeting FOXO proteins. Trends Mol Med. 2008;14:219–27.
• 10. Maiese K, Chong ZZ, Shang YC, Hou J. A “FOXO” in sight: targeting Foxo proteins from conception to cancer. Med Res Rev. 2009;29:395–418.
• 11. Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, ve ark. Sirt1 protects againts oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression. Biochem Biophys Res Commun. 2008;372:51–6.
• 12. Chong ZZ, Lin SH, Li F, Maiese K. The sirtuin inhibitor nicotinamide enhances neuronal cell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrial associated “anti-apoptotic” pathways. Curr Neurovasc Res. 2005;2:271–85.
• 13. Chong ZZ, Maiese K. Enhanced tolerance against early and late apoptotic oxidative stress in mammalian neurons through nicotinamidase and sirtuin mediated pathways. Curr Neurovasc Res. 2008;5:159–70.
• 14. Donmez G, Arun A, Chung CY, McLean PJ, Lindquist S, Guarente L. SIRT1 protects against a-synuclein aggregation by activating molecular chaperones. J Neurosci. 2012;32:124–32.
• 15. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967;17:427–42.
• 16. Donmez G, Outeiro T. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Mol Med. 2013;5(3):344–52.
• 17. Duty S, Jenner P. Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol. 2011;164(4):1357–91.
• 18. Jagmag SA, Tripathi N, Shukla SD, Maiti S, Khurana S. Evaluation of models of Parkinson’s disease. Front Neurosci. 2015;9:503.
• 19. Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med. 2013;62:90–101.
• 20. Lang AE, Obeso JA. Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol. 2004;3:309–16.
• 21. De Virgilio A, Greco A, Fabbrini G, Inghilleri M, Rizzo MI, Gallo A, ve ark. Parkinson’s disease: autoimmunity and neuroinflammation. Autoimmun Rev. 2016;15:1005–11.
• 22. Gasser T. Genetics of Parkinson’s disease. Ann Neurol. 1998;44:53–7.
• 23. Lill CM. Genetics of Parkinson’s disease. Mol Cell Probes. 2016;30(6):386–96.
• 24. Balestrino R, Schapira AH. Parkinson disease. Eur J Neurol. 2020;27(1):27–42.
• 25. Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;1:1–15.
• 26. Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinson’s disease. Ann Neurol. 2003;53(ek 3):S16–S25.
• 27. Cookson MR, Xiromerisiou G, Singleton A. How genetics research in Parkinson’s disease is enhancing understanding of the common idiopathic forms of the disease. Curr Opin Neurol. 2005;18:706–11.
• 28. Lesage S, Brice A. Parkinson’s disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18(R1):R48–R59.
• 29. Madegowda RH, Kishore A, Anand A. Mutational screening of the Parkin gene among South Indians with early onset Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2005;76:1588–90.
• 30. Chaudhary S, Behari M, Dihana M, Swaminath PV, Govindappa ST, Jayaram S, ve ark. Parkin mutations in familial and sporadic Parkinson’s disease among Indians. Parkinsonism Relat Disord. 2006;12:239–45.
• 31. Biswas A, Gupta A, Naiya T, Das G, Neogi R, Datta S, ve ark. Molecular pathogenesis of Parkinson’s disease: identification of mutations in the Parkin gene in Indian patients. Parkinsonism Relat Disord. 2006;12:420–6.
• 32. Vinish M, Prabhakar S, Khullar M, Verma I, Anand A. Genetic screening reveals high frequency of PARK2 mutations and reduced Parkin expression conferring risk for Parkinsonism in North West India. J Neurol Neurosurg Psychiatry. 2010;81:166–70.
• 33. Padmaja MV, Jayaraman M, Srinivasan AV, Srisailapathy CR, Ramesh A. PARK2 gene mutations in early onset Parkinson’s disease patients of South India. Neurosci Lett. 2012;523:145–7.
• 34. Abbas MM, Govindappa ST, Sudhaman S, Thelma BK, Juyal RC, Behari M, ve ark. Early onset Parkinson’s disease due to DJ1 mutations: an Indian study. Parkinsonism Relat Disord. 2016;32:20–4.
• 35. Gilks WP, Abou‑Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, ve ark. A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet. 2005;365:415–6.
• 36. Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinson’s disease. Ann Neurol. 2003;53(ek 3):S16–S25.
• 37. Chu CT. A pivotal role for PINK 1 and autophagy in mitochondrial quality control: implications for Parkinson disease. Hum Mol Genet. 2010;19:28–37.
• 38. Dodson MW, Guo M. Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson’s disease. Curr Opin Neurobiol. 2007;17(3):331–7.
• 39. Cristóvão AC, Guhathakurta S, Bok E, Je G, Yoo SD, Choi DH, ve ark. NADPH oxidase 1 mediates α-synucleinopathy in Parkinson’s disease. J Neurosci. 2012;32(42):14465–77.
• 40. Shimoyama Y, Mitsuda Y, Tsuruta Y, Suzuki K, Hamajima N, Niwa T. SIRTUIN 1 gene polymorphisms are associated with cholesterol metabolism and coronary artery calcification in Japanese hemodialysis patients. J Ren Nutr. 2012;22:114–9.
• 41. Maeda S, Koya D, Araki SI, Babazono T, Umezono T, Toyoda M, ve ark. Association between single nucleotide polymorphisms within genes encoding sirtuin families and diabetic nephropathy in Japanese subjects with type 2 diabetes. Clin Exp Nephrol. 2011;15(3):381–90.
• 42. Kim YR, Kim SS, Yoo NJ, Lee SH. Frameshift mutation of SIRT1 gene in gastric and colorectal carcinomas with microsatellite instability. APMIS. 2010;118:81–2.
• 43. Edgunlu TG, Celik SK, Emre U, Unal AE, Dursun A. Variant analysis of the sirtuin (SIRT1) gene in multiple sclerosis. Kuwait Med J. 2013;45:313–8.
• 44. Dong Y, Guo T, Traurig M, Mason CC, Kobes S, Perez J, ve ark. SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians. Mol Genet Metab. 2011;104(4):661–5.
• 45. Kalemci S, Edgunlu TG, Kara M, Turkcu UO, Cetin ES, Zeybek A. Sirtuin gene polymorphisms are associated with chronic obstructive pulmonary disease in patients in Muğla province. Kardiochir Torakochirurgia Pol. 2014;11(3):306–10.
• 46. Zhang A, Wang H, Qin X, Pang S, Yan B. Genetic analysis of SIRT1 gene promoter in sporadic Parkinson’s disease. Biochem Biophys Res Commun. 2012;422(4):693–6.
• 47. Jesús S, Gómez-Garre P, Carrillo F, Cáceres-Redondo MT, Huertas-Fernández I, Bernal-Bernal I, ve ark. Genetic association of sirtuin genes and Parkinson’s disease. J Neurol. 2013;260:2237–41.