INVESTIGATION OF THE RELATIONSHIP BETWEEN PARKINSON'S DISEASE AND TIRAP GENE POLYMORPHISM
Year 2024,
, 103 - 109, 18.03.2024
Merve Kır Kayan
,
Nilüfer Şahin Calapoğlu
Abstract
Objective
Parkinson's disease (PD) is a progressive disease
characterized by the loss of dopamine-producing cells
in the brain. A protein called α-synuclein accumulates
in the brain tissue of patients with PD and causes
neuroinflammation. Neuroinflammation involves the
activation of immune system cells in the brain and
the release of inflammation-related molecules. The
Toll Like Receptors (TLRs) involved in this process
recognize pathogens and damaged cells and initiate
the immune response. In this study, we aimed to
investigate the association of the polymorphic allele on the Toll/IL-1 receptor-associated protein (TIRAP) gene
region, an adaptor protein involved in the TLR signaling
pathway, in patients with PD and in the control group.
Material and Method
39 PD patients and 40 healthy individuals participated
in the study. Blood samples were taken from the
participants and DNA isolation was performed. TIRAP
rs8177374 (975C/T) polymorphism was determined by
PCR and RFLP methods.
Results
T allele frequency was found to be 0.218 in PD patients
and 0.200 in the control group. C allele frequency and
CC genotype frequency were found to be high in both
groups. F value was found to be 0,128 in PD patients
and 0,250 in the control group. OR value was 1.115;
CI value was [0,517-2,402]. Total OR=1,508; P=0,758.
Conclusion
No statistically significant association was found
between TIRAP polymorphism and PD. It was
concluded that TIRAP polymorphism is not a risk factor
in PD patients.
Project Number
4777-YL1-16
References
- 1. Adams RD, Victor M, Ropper AH, Daroff RB. Principles of
neurology. LWW; 1997.
- 2. Ham RJ. Primary care geriatrics: a case-based approach: Elsevier
Health Sciences; 2007.
- 3. Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White III CL, et
al. Multi-organ distribution of phosphorylated α-synuclein histopathology
in subjects with Lewy body disorders. Acta neuropathologica.
2010;119(6):689-702.
- 4. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson’s
disease: lesions in dorsal horn layer I, involvement
of parasympathetic and sympathetic pre-and postganglionic
neurons. Acta neuropathologica. 2007;113(4):421-9.
- 5. Kalia LV, Lang AE. Parkinson disease in 2015: evolving basic,
pathological and clinical concepts in PD. Nature reviews
Neurology. 2016;12(2):65.
- 6. Sechi LA, Caggiu E, Arru G. Inflammation, infectious triggers
and Parkinson disease. Frontiers in Neurology. 2019;10:122.
- 7. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M,
et al. Interleukin-1β, interleukin-6, epidermal growth factor and
transforming growth factor-α are elevated in the brain from parkinsonian
patients. Neuroscience letters. 1994;180(2):147-50.
- 8. Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu
T. Tumor necrosis factor-α (TNF-α) increases both in the
brain and in the cerebrospinal fluid from parkinsonian patients.
Neuroscience letters. 1994;165(1-2):208-10.
- 9. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory
mechanisms in Parkinson's disease: potential environmental
triggers, pathways, and targets for early therapeutic intervention.
Experimental neurology. 2007;208(1):1-25.
- 10. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Lee Mosley
R. Neuroprotective activities of CD4+ CD25+ regulatory T cells
in an animal model of Parkinson’s disease. Journal of leukocyte
biology. 2007;82(5):1083-94.
- 11. Reynolds AD, Glanzer JG, Kadiu I, Ricardo‐Dukelow M, Chaudhuri
A, Ciborowski P, et al. Nitrated alpha‐synuclein‐activated
microglial profiling for Parkinson’s disease. Journal of Neurochemistry. 2008;104(6):1504-25.
- 12. Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski
P, et al. Nitrated alpha-synuclein and microglial neuroregulatory
activities. Journal of Neuroimmune Pharmacology.
2008;3(2):59-74.
- 13. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated
α-synuclein activates microglia: a process leading to
disease progression in Parkinson’s disease. The FASEB Journal.
2005;19(6):533-42.
- 14. Gong L, Wang H, Sun X, Liu C, Duan C, Cai R, et al. Toll‐Interleukin
1 Receptor domain‐containing adaptor protein positively
regulates BV 2 cell M1 polarization. European Journal of
Neuroscience. 2016;43(12):1674-82.
- 15. Underhill DM, Ozinsky A. Toll-like receptors: key mediators
of microbe detection. Current opinion in immunology.
2002;14(1):103-10.
- 16. Akira S, Takeda K. Toll-like receptor signalling. Nature reviews
immunology. 2004;4(7):499-511.
- 17. Bonizzi G, Karin M. The two NF-κB activation pathways and
their role in innate and adaptive immunity. Trends in immunology.
2004;25(6):280-8.
- 18. Muzio M, Polentarutti N, Bosisio D, Kumar PM, Mantovani A.
Toll-like receptor family and signalling pathway. Biochemical
Society Transactions. 2000;28(5):563-6.
- 19. Naderi M, Hashemi M, Pourmontaseri Z, Eskandari-Nasab
E, Bahari G, Taheri M. TIRAP rs8177374 gene polymorphism
increased the risk of pulmonary tuberculosis in Zahedan,
southeast Iran. Asian Pacific journal of tropical medicine.
2014;7(6):451-5.
- 20. Bechtel CP, Gebhart JJ, Tatro JM, Kiss-Toth E, Wilkinson JM,
Greenfield EM. Particle-induced osteolysis is mediated by
TIRAP/Mal in vitro and in vivo: dependence on adherent pathogen-
associated molecular patterns. JBJS. 2016;98(4):285-94.
- 21. Wirdefeldt K, Adami H-O, Cole P, Trichopoulos D, Mandel J.
Epidemiology and etiology of Parkinson’s disease: a review of
the evidence. European journal of epidemiology. 2011;26(1):1.
- 22. Irizarry MC, Growdon W, Gomez-Isla T, Newell K, George JM,
Clayton DF, et al. Nigral and cortical Lewy bodies and dystrophic
nigral neurites in Parkinson's disease and cortical Lewy
body disease contain α-synuclein immunoreactivity. Journal of
Neuropathology & Experimental Neurology. 1998;57(4):334-7.
- 23. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert
M. α-Synuclein in filamentous inclusions of Lewy bodies from
Parkinson’s disease and dementia with Lewy bodies. Proceedings
of the National Academy of Sciences. 1998;95(11):6469-73.
- 24. Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross
CA, Takahashi H. Synphilin‐1 is present in Lewy bodies in Parkinson's
disease. Annals of Neurology: Official Journal of the
American Neurological Association and the Child Neurology
Society. 2000;47(4):521-3.
- 25. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara
Y. Lewy bodies are ubiquitinated. Acta neuropathologica.
1988;75(4):345-53.
- 26. Braak H, Del Tredici K, Rüb U, De Vos RA, Steur ENJ, Braak
E. Staging of brain pathology related to sporadic Parkinson’s
disease. Neurobiology of Aging. 2003;24(2):197-211.
- 27. Amor S, Woodroofe MN. Innate and adaptive immune
responses in neurodegeneration and repair. Immunology.
2014;141(3):287-91.
- 28. Cardoso V, Chesné J, Ribeiro H, García-Cassani B, Carvalho
T, Bouchery T, et al. Neuronal regulation of type 2 innate lymphoid
cells via neuromedin U. Nature. 2017;549(7671):277.
- 29. Horng T, Barton GM, Flavell RA, Medzhitov R. The adaptor molecule
TIRAP provides signalling specificity for Toll-like receptors.
Nature. 2002;420(6913):329.
- 30. Cheng P, Zhang J, Wu Y, Liu W, Zhu J, Chen Z, et al. 5-HTTLPR
polymorphism and depression risk in Parkinson's disease: an
updated meta-analysis. Acta Neurol Belg. 2021;121(4):933-40.
- 31. Fang J, Hou B, Liu H, Zhang X, Wang J, Zhou C, et al. Association
between SNCA rs2736990 polymorphism and Parkinson's
disease: a meta-analysis. Neurosci Lett. 2017;658:102-7.
- 32. Ma ZG, He F, Xu J. Quantitative assessment of the association
between GAK rs1564282 C/T polymorphism and the risk
of Parkinson's disease. J Clin Neurosci. 2015;22(7):1077-80.
- 33. Selvaraj P, Harishankar M, Singh B, Jawahar M, Banurekha
V. Toll-like receptor and TIRAP gene polymorphisms in pulmonary
tuberculosis patients of South India. Tuberculosis.
2010;90(5):306-10.
- 34. Miao R, Li J, Sun Z, Xu F, Shen H. Meta-analysis on the association
of TIRAP S180L variant and tuberculosis susceptibility.
Tuberculosis. 2011;91(3):268-72.
- 35. Rani A, Nawaz SK, Irfan S, Arshad M, Bashir R, Shaheen N.
Role of MyD88-adaptor-like gene polymorphism rs8177374 in
modulation of malaria severity in the Pakistani population. The
Brazilian Journal of Infectious Diseases. 2017;21(4):418-23.
- 36. Karody V, Le M, Nelson S, Meskin K, Klemm S, Simpson P, et
al. A TIR domain receptor–associated protein (TIRAP) variant
SNP (rs8177374) confers protection against premature birth.
Journal of Perinatology. 2013;33(5):341.
- 37. Degirmenci I, Ozbayer C, Kebapci MN, Kurt H, Colak E, Gunes
HV. Common variants of genes encoding TLR4 and TLR4 pathway
members TIRAP and IRAK1 are effective on MCP1, IL6,
IL1β, and TNFα levels in type 2 diabetes and insulin resistance.
Inflammation Research. 2019:1-14.
- 38. Fulgione A, Di Matteo A, Contaldi F, Manco R, Ianniello F, Incerti
G, et al. Epistatic interaction between MyD88 and TIRAP against
Helicobacter pylori. FEBS Letters. 2016;590(14):2127-37.
PARKİNSON HASTALIĞI İLE TIRAP GEN POLİMORFİZMİ ARASINDAKİ İLİŞKİNİN ARAŞTIRILMASI
Year 2024,
, 103 - 109, 18.03.2024
Merve Kır Kayan
,
Nilüfer Şahin Calapoğlu
Abstract
Amaç
Parkinson hastalığı (PH), beyinde dopamin üreten
hücrelerin kaybıyla ilerleyen bir hastalıktır. PH’li hastaların
beyin dokularında α-sinüklein adlı bir protein
birikir ve nöroinflamasyona neden olur. Nöroinflamasyon,
beyindeki bağışıklık sistemi hücrelerinin aktivasyonu
ve iltihaplanma ile ilgili moleküllerin salınımını
içerir. Bu süreçte rol oynayan Toll Like Reseptör
(TLR)’ler patojenleri ve hasarlı hücreleri tanıyarak
bağışıklık yanıtını başlatır. Bu çalışmada, TLR sinyal
yolağında yer alan bir adaptör protein olan Toll/IL-1
reseptör ilişkili protein (TIRAP) gen bölgesi üzerindeki
polimorfik allelin PH’li hastalarda ve kontrol grubunda
karşılaştırmalı olarak ilişkisini araştırmayı amaçladık.
Gereç ve Yöntem
Çalışmaya 39 PH hastası ve 40 sağlıklı kişi katıldı.
Katılımcılardan kan örnekleri alınarak DNA izolasyonu
yapıldı. TIRAP rs8177374 (975C/T) polimorfizmi
PCR ve RFLP yöntemleri ile belirlendi.
Bulgular
T allel frekansı PH hastalarında 0,218; kontrol grubunda
ise 0,200 olarak bulundu. C allel frekansı ve
CC genotip frekansı her iki grupta da yüksek bulundu.
F değeri PH hastalarında 0,128; kontrol grubunda
ise 0,250 olarak bulundu. OR değeri 1,115; CI değeri
ise [0,517-2,402] olarak bulundu. Total OR=1,508;
P=0,758 olarak bulundu.
Sonuç
TIRAP polimorfizmi ile PH arasında istatistiksel olarak
anlamlı bir ilişki bulunmadı. TIRAP polimorfizminin PH
hastalarında risk faktörü olmadığı sonucuna varıldı.
Ethical Statement
Süleyman Demirel Üniversitesi Tıp Fakültesi Klinik Araştırmalar Etik Kurulu Başkanlığı’ndan 15.07.2015 tarihli ve 166 sayılı kararı ile etik kurul izni alınarak gerçekleştirildi. Çalışma Helsinki Deklarasyonuna uygun olarak yürütülmüştür.
Supporting Institution
Süleyman Demirel Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi
Project Number
4777-YL1-16
References
- 1. Adams RD, Victor M, Ropper AH, Daroff RB. Principles of
neurology. LWW; 1997.
- 2. Ham RJ. Primary care geriatrics: a case-based approach: Elsevier
Health Sciences; 2007.
- 3. Beach TG, Adler CH, Sue LI, Vedders L, Lue L, White III CL, et
al. Multi-organ distribution of phosphorylated α-synuclein histopathology
in subjects with Lewy body disorders. Acta neuropathologica.
2010;119(6):689-702.
- 4. Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson’s
disease: lesions in dorsal horn layer I, involvement
of parasympathetic and sympathetic pre-and postganglionic
neurons. Acta neuropathologica. 2007;113(4):421-9.
- 5. Kalia LV, Lang AE. Parkinson disease in 2015: evolving basic,
pathological and clinical concepts in PD. Nature reviews
Neurology. 2016;12(2):65.
- 6. Sechi LA, Caggiu E, Arru G. Inflammation, infectious triggers
and Parkinson disease. Frontiers in Neurology. 2019;10:122.
- 7. Mogi M, Harada M, Kondo T, Riederer P, Inagaki H, Minami M,
et al. Interleukin-1β, interleukin-6, epidermal growth factor and
transforming growth factor-α are elevated in the brain from parkinsonian
patients. Neuroscience letters. 1994;180(2):147-50.
- 8. Mogi M, Harada M, Riederer P, Narabayashi H, Fujita K, Nagatsu
T. Tumor necrosis factor-α (TNF-α) increases both in the
brain and in the cerebrospinal fluid from parkinsonian patients.
Neuroscience letters. 1994;165(1-2):208-10.
- 9. Tansey MG, McCoy MK, Frank-Cannon TC. Neuroinflammatory
mechanisms in Parkinson's disease: potential environmental
triggers, pathways, and targets for early therapeutic intervention.
Experimental neurology. 2007;208(1):1-25.
- 10. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Lee Mosley
R. Neuroprotective activities of CD4+ CD25+ regulatory T cells
in an animal model of Parkinson’s disease. Journal of leukocyte
biology. 2007;82(5):1083-94.
- 11. Reynolds AD, Glanzer JG, Kadiu I, Ricardo‐Dukelow M, Chaudhuri
A, Ciborowski P, et al. Nitrated alpha‐synuclein‐activated
microglial profiling for Parkinson’s disease. Journal of Neurochemistry. 2008;104(6):1504-25.
- 12. Reynolds AD, Kadiu I, Garg SK, Glanzer JG, Nordgren T, Ciborowski
P, et al. Nitrated alpha-synuclein and microglial neuroregulatory
activities. Journal of Neuroimmune Pharmacology.
2008;3(2):59-74.
- 13. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated
α-synuclein activates microglia: a process leading to
disease progression in Parkinson’s disease. The FASEB Journal.
2005;19(6):533-42.
- 14. Gong L, Wang H, Sun X, Liu C, Duan C, Cai R, et al. Toll‐Interleukin
1 Receptor domain‐containing adaptor protein positively
regulates BV 2 cell M1 polarization. European Journal of
Neuroscience. 2016;43(12):1674-82.
- 15. Underhill DM, Ozinsky A. Toll-like receptors: key mediators
of microbe detection. Current opinion in immunology.
2002;14(1):103-10.
- 16. Akira S, Takeda K. Toll-like receptor signalling. Nature reviews
immunology. 2004;4(7):499-511.
- 17. Bonizzi G, Karin M. The two NF-κB activation pathways and
their role in innate and adaptive immunity. Trends in immunology.
2004;25(6):280-8.
- 18. Muzio M, Polentarutti N, Bosisio D, Kumar PM, Mantovani A.
Toll-like receptor family and signalling pathway. Biochemical
Society Transactions. 2000;28(5):563-6.
- 19. Naderi M, Hashemi M, Pourmontaseri Z, Eskandari-Nasab
E, Bahari G, Taheri M. TIRAP rs8177374 gene polymorphism
increased the risk of pulmonary tuberculosis in Zahedan,
southeast Iran. Asian Pacific journal of tropical medicine.
2014;7(6):451-5.
- 20. Bechtel CP, Gebhart JJ, Tatro JM, Kiss-Toth E, Wilkinson JM,
Greenfield EM. Particle-induced osteolysis is mediated by
TIRAP/Mal in vitro and in vivo: dependence on adherent pathogen-
associated molecular patterns. JBJS. 2016;98(4):285-94.
- 21. Wirdefeldt K, Adami H-O, Cole P, Trichopoulos D, Mandel J.
Epidemiology and etiology of Parkinson’s disease: a review of
the evidence. European journal of epidemiology. 2011;26(1):1.
- 22. Irizarry MC, Growdon W, Gomez-Isla T, Newell K, George JM,
Clayton DF, et al. Nigral and cortical Lewy bodies and dystrophic
nigral neurites in Parkinson's disease and cortical Lewy
body disease contain α-synuclein immunoreactivity. Journal of
Neuropathology & Experimental Neurology. 1998;57(4):334-7.
- 23. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert
M. α-Synuclein in filamentous inclusions of Lewy bodies from
Parkinson’s disease and dementia with Lewy bodies. Proceedings
of the National Academy of Sciences. 1998;95(11):6469-73.
- 24. Wakabayashi K, Engelender S, Yoshimoto M, Tsuji S, Ross
CA, Takahashi H. Synphilin‐1 is present in Lewy bodies in Parkinson's
disease. Annals of Neurology: Official Journal of the
American Neurological Association and the Child Neurology
Society. 2000;47(4):521-3.
- 25. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara
Y. Lewy bodies are ubiquitinated. Acta neuropathologica.
1988;75(4):345-53.
- 26. Braak H, Del Tredici K, Rüb U, De Vos RA, Steur ENJ, Braak
E. Staging of brain pathology related to sporadic Parkinson’s
disease. Neurobiology of Aging. 2003;24(2):197-211.
- 27. Amor S, Woodroofe MN. Innate and adaptive immune
responses in neurodegeneration and repair. Immunology.
2014;141(3):287-91.
- 28. Cardoso V, Chesné J, Ribeiro H, García-Cassani B, Carvalho
T, Bouchery T, et al. Neuronal regulation of type 2 innate lymphoid
cells via neuromedin U. Nature. 2017;549(7671):277.
- 29. Horng T, Barton GM, Flavell RA, Medzhitov R. The adaptor molecule
TIRAP provides signalling specificity for Toll-like receptors.
Nature. 2002;420(6913):329.
- 30. Cheng P, Zhang J, Wu Y, Liu W, Zhu J, Chen Z, et al. 5-HTTLPR
polymorphism and depression risk in Parkinson's disease: an
updated meta-analysis. Acta Neurol Belg. 2021;121(4):933-40.
- 31. Fang J, Hou B, Liu H, Zhang X, Wang J, Zhou C, et al. Association
between SNCA rs2736990 polymorphism and Parkinson's
disease: a meta-analysis. Neurosci Lett. 2017;658:102-7.
- 32. Ma ZG, He F, Xu J. Quantitative assessment of the association
between GAK rs1564282 C/T polymorphism and the risk
of Parkinson's disease. J Clin Neurosci. 2015;22(7):1077-80.
- 33. Selvaraj P, Harishankar M, Singh B, Jawahar M, Banurekha
V. Toll-like receptor and TIRAP gene polymorphisms in pulmonary
tuberculosis patients of South India. Tuberculosis.
2010;90(5):306-10.
- 34. Miao R, Li J, Sun Z, Xu F, Shen H. Meta-analysis on the association
of TIRAP S180L variant and tuberculosis susceptibility.
Tuberculosis. 2011;91(3):268-72.
- 35. Rani A, Nawaz SK, Irfan S, Arshad M, Bashir R, Shaheen N.
Role of MyD88-adaptor-like gene polymorphism rs8177374 in
modulation of malaria severity in the Pakistani population. The
Brazilian Journal of Infectious Diseases. 2017;21(4):418-23.
- 36. Karody V, Le M, Nelson S, Meskin K, Klemm S, Simpson P, et
al. A TIR domain receptor–associated protein (TIRAP) variant
SNP (rs8177374) confers protection against premature birth.
Journal of Perinatology. 2013;33(5):341.
- 37. Degirmenci I, Ozbayer C, Kebapci MN, Kurt H, Colak E, Gunes
HV. Common variants of genes encoding TLR4 and TLR4 pathway
members TIRAP and IRAK1 are effective on MCP1, IL6,
IL1β, and TNFα levels in type 2 diabetes and insulin resistance.
Inflammation Research. 2019:1-14.
- 38. Fulgione A, Di Matteo A, Contaldi F, Manco R, Ianniello F, Incerti
G, et al. Epistatic interaction between MyD88 and TIRAP against
Helicobacter pylori. FEBS Letters. 2016;590(14):2127-37.