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IN SILICO ANALYSIS OF THE POTENTIAL ROLE OF SRY GENE IN PARKINSON’S DISEASE

Year 2023, , 19 - 24, 14.03.2023
https://doi.org/10.17343/sdutfd.1166918

Abstract

Objective
Parkinson’s disease (PD) is the most common movement
disorder and is caused by the loss of dopaminergic
neurons in the substantia nigra. The first
motor symptoms of PD begin to appear when more
than 60% of dopaminergic neurons are already lost.
Although the etiology of PD is not fully understood,
PD is believed to result from the complex interactions
between genetic and environmental factors. Previous
studies demonstrated that men are at least 1.5 times
more likely to develop PD than women. The current
kulstudy
aimed to investigate whether SRY, a chromosome
gene, plays a role in the pathogenesis of PD
using in silico methods.
Material and Method
The mRNA expression of SRY in different human tissues
was analyzed using the Human Protein Atlas
(HPA). The interactions between SRY and PD-related
genes were analyzed using the STRING and
GeneMANIA databases. The JASPAR database was
used to determine the putative binding sites of SRY in
the promoter regions of some PD-related genes. Finally,
the BioGRID and GeneMANIA databases were
used to identify the key genes that interact with SRY.
Results
In silico analyses revealed that there are SRY binding
sites in the promoter regions of some PD-associated
genes and that SRY can regulate androgen receptor
(AR) signaling.
Conclusion
These findings suggest that SRY may play a role in
the pathogenesis of PD and may thus serve as a molecular
target for developing new therapeutic strategies
against PD.

References

  • 1. Vitek JL, Johnson LA. Understanding Parkinson's disease and deep brain stimulation: Role of monkey models. Proc Natl Acad Sci U S A. 2019 Dec 23;116(52):26259–65
  • 2. Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, Weintraub D. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021 Jul 1;7(1):47
  • 3. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. 2011 Jun;26 Suppl 1: S1-58
  • 4. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009 May;8(5):464-74
  • 5. Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2: R183-94
  • 6. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003 Sep 11;39(6):889-909
  • 7. Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson's disease: proximal triggers, distal effectors, and final steps. Apoptosis. 2009 Apr;14(4):478-500
  • 8. Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J. Are men at greater risk for Parkinson's disease than women? J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):637-9
  • 9. Ferrari S, Harley VR, Pontiggia A, Goodfellow PN, Lovell-Badge R, Bianchi ME. SRY, like HMG1, recognizes sharp angles in DNA. EMBO J. 1992 Dec;11(12):4497-506
  • 10. Czech DP, Lee J, Sim H, Parish CL, Vilain E, Harley VR. The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism. J Neurochem. 2012 Jul;122(2):260-71
  • 11. Lee J, Pinares-Garcia P, Loke H, Ham S, Vilain E, Harley VR. Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson's disease. Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16577-16582
  • 12. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F. Proteomics. Tissue-based map of the human proteome. Science. 2015 Jan 23;347(6220):1260419
  • 13. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
  • 14. Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, Maitland A, Mostafavi S, Montojo J, Shao Q, Wright G, Bader GD, Morris Q. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010 Jul;38(Web Server issue):W214-20
  • 15. Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
  • 16. Dreos R, Ambrosini G, Périer RC, Bucher P. The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res. 2015 Jan;43(Database issue):D92-6
  • 17. Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson's disease. Lancet Neurol. 2020 Feb;19(2):170-178
  • 18. Yuan X, Lu ML, Li T, Balk SP. SRY interacts with and negatively regulates androgen receptor transcriptional activity. J Biol Chem. 2001 Dec 7;276(49):46647-54
  • 19. Bianchi VE, Rizzi L, Bresciani E, Omeljaniuk RJ, Torsello A. Androgen Therapy in Neurodegenerative Diseases. J Endocr Soc. 2020 Aug 21;4(11):bvaa120
  • 20. Espay AJ, Pagan FL, Walter BL, Morgan JC, Elmer LW, Waters CH, Agarwal P, Dhall R, Ondo WG, Klos KJ, Silver DE. Optimizing extended-release carbidopa/levodopa in Parkinson disease: Consensus on conversion from standard therapy. Neurol Clin Pract. 2017 Feb;7(1):86-93
  • 21. Koopman P, Münsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature. 1990 Nov 29;348(6300):450-2
  • 22. Lahr G, Maxson SC, Mayer A, Just W, Pilgrim C, Reisert I. Transcription of the Y chromosomal gene, Sry, in adult mouse brain. Brain Res Mol Brain Res. 1995 Oct;33(1):179-82
  • 23. Mayer A, Lahr G, Swaab DF, Pilgrim C, Reisert I. The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics. 1998 Aug;1(4):281-8
  • 24. Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 2006 Feb 21;16(4):415-20
  • 25. Di Fonzo A, Rohé CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V; Italian Parkinson Genetics Network. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):412-5
  • 26. Cookson MR. Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med. 2012 Sep 1;2(9):a009415
  • 27. Okun MS, Crucian GP, Fischer L, Walter BL, Testa CM, Vitek JL, DeLong MR, Hanfelt J, Huang X. Testosterone deficiency in a Parkinson's disease clinic: results of a survey. J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):165-6
  • 28. Mitchell E, Thomas D, Burnet R. Testosterone improves motor function in Parkinson's disease. J Clin Neurosci. 2006 Jan;13(1):133-6
  • 29. Louissaint A Jr, Rao S, Leventhal C, Goldman SA. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron. 2002 Jun 13;34(6):945-60
  • 30. Chang E, Wang J. Brain-derived neurotrophic factor attenuates cognitive impairment and motor deficits in a mouse model of Parkinson's disease. Brain Behav. 2021 Aug;11(8):e2251
  • 31. Klein RL, Lewis MH, Muzyczka N, Meyer EM. Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer. Brain Res. 1999 Nov 20;847(2):314-20
  • 32. Tsukahara T, Takeda M, Shimohama S, Ohara O, Hashimoto N. Effects of brain-derived neurotrophic factor on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys. Neurosurgery. 1995 Oct;37(4):733-9; discussion 739-41

SRY GENİNİN PARKİNSON HASTALIĞINDAKİ POTANSİYEL ROLÜNÜN İN SİLİKO ANALİZİ

Year 2023, , 19 - 24, 14.03.2023
https://doi.org/10.17343/sdutfd.1166918

Abstract

Amaç
Parkinson hastalığı (PH) en sık görülen hareket hastalığıdır
ve substansiya nigra bölgesindeki dopaminerjik
nöronların kaybından kaynaklanmaktadır. PH’nin ilk
motor semptomları ortaya çıkmaya başladığında dopaminerjik
nöronların %60’ından fazlası zaten ölmüştür.
PH’nin etiyolojisi tam olarak anlaşılmamış olsa
da, PH’nin genetik ve çevresel faktörler arasındaki
kompleks etkileşimler sonucu oluştuğuna inanılmaktadır.
Önceki çalışmalar erkeklerin PH’ye yakalanma
olasılığının kadınlara göre en az 1,5 kat daha fazla
olduğunu göstermiştir. Bu çalışma, bir Y kromozomu
geni olan SRY’nin PH’nin patogenezinde bir rol oynayıp
oynamadığını in siliko yöntemlerle araştırmayı
amaçlamıştır.
Gereç ve Yöntem
Farklı insan dokularındaki SRY mRNA ekspresyonu
İnsan Protein Atlas (HPA)’yı kullanarak analiz edilmiştir.
SRY ve PH ile ilişkili genler arasındaki etkileşimler
STRING ve GeneMANIA veri tabanlarını kullanarak
incelenmiştir. JASPAR veri tabanı, PH ile ilişkili bazı
genlerin promotör bölgelerindeki muhtemel SRY bağlanma
noktalarını belirlemek için kullanılmıştır. Son
olarak, SRY ile etkileşim halindeki anahtar genleri belirlemek
için BioGRID ve GeneMANIA veri tabanları
kullanılmıştır.
Bulgular
İn siliko analizler PH ile ilişkili bazı genlerin promotör
bölgelerinde SRY bağlanma noktası olduğunu ve SRY’nin
androjen reseptör (AR) sinyalini düzenleyebileceğini
ortaya çıkarmıştır.
Sonuç
Bu bulgular SRY’nin PH’nin patogenezinde rol oynayabileceğini
ve bundan dolayı da PH’ye karşı yeni terapötik
stratejiler geliştirmek için moleküler bir hedef
vazifesi görebileceğini önermektedir.

References

  • 1. Vitek JL, Johnson LA. Understanding Parkinson's disease and deep brain stimulation: Role of monkey models. Proc Natl Acad Sci U S A. 2019 Dec 23;116(52):26259–65
  • 2. Aarsland D, Batzu L, Halliday GM, Geurtsen GJ, Ballard C, Ray Chaudhuri K, Weintraub D. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021 Jul 1;7(1):47
  • 3. Wirdefeldt K, Adami HO, Cole P, Trichopoulos D, Mandel J. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. 2011 Jun;26 Suppl 1: S1-58
  • 4. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson's disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009 May;8(5):464-74
  • 5. Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet. 2007 Oct 15;16 Spec No. 2: R183-94
  • 6. Dauer W, Przedborski S. Parkinson's disease: mechanisms and models. Neuron. 2003 Sep 11;39(6):889-909
  • 7. Levy OA, Malagelada C, Greene LA. Cell death pathways in Parkinson's disease: proximal triggers, distal effectors, and final steps. Apoptosis. 2009 Apr;14(4):478-500
  • 8. Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J. Are men at greater risk for Parkinson's disease than women? J Neurol Neurosurg Psychiatry. 2004 Apr;75(4):637-9
  • 9. Ferrari S, Harley VR, Pontiggia A, Goodfellow PN, Lovell-Badge R, Bianchi ME. SRY, like HMG1, recognizes sharp angles in DNA. EMBO J. 1992 Dec;11(12):4497-506
  • 10. Czech DP, Lee J, Sim H, Parish CL, Vilain E, Harley VR. The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism. J Neurochem. 2012 Jul;122(2):260-71
  • 11. Lee J, Pinares-Garcia P, Loke H, Ham S, Vilain E, Harley VR. Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson's disease. Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16577-16582
  • 12. Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson Å, Kampf C, Sjöstedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Pontén F. Proteomics. Tissue-based map of the human proteome. Science. 2015 Jan 23;347(6220):1260419
  • 13. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
  • 14. Warde-Farley D, Donaldson SL, Comes O, Zuberi K, Badrawi R, Chao P, Franz M, Grouios C, Kazi F, Lopes CT, Maitland A, Mostafavi S, Montojo J, Shao Q, Wright G, Bader GD, Morris Q. The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function. Nucleic Acids Res. 2010 Jul;38(Web Server issue):W214-20
  • 15. Stark C, Breitkreutz BJ, Reguly T, Boucher L, Breitkreutz A, Tyers M. BioGRID: a general repository for interaction datasets. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
  • 16. Dreos R, Ambrosini G, Périer RC, Bucher P. The Eukaryotic Promoter Database: expansion of EPDnew and new promoter analysis tools. Nucleic Acids Res. 2015 Jan;43(Database issue):D92-6
  • 17. Blauwendraat C, Nalls MA, Singleton AB. The genetic architecture of Parkinson's disease. Lancet Neurol. 2020 Feb;19(2):170-178
  • 18. Yuan X, Lu ML, Li T, Balk SP. SRY interacts with and negatively regulates androgen receptor transcriptional activity. J Biol Chem. 2001 Dec 7;276(49):46647-54
  • 19. Bianchi VE, Rizzi L, Bresciani E, Omeljaniuk RJ, Torsello A. Androgen Therapy in Neurodegenerative Diseases. J Endocr Soc. 2020 Aug 21;4(11):bvaa120
  • 20. Espay AJ, Pagan FL, Walter BL, Morgan JC, Elmer LW, Waters CH, Agarwal P, Dhall R, Ondo WG, Klos KJ, Silver DE. Optimizing extended-release carbidopa/levodopa in Parkinson disease: Consensus on conversion from standard therapy. Neurol Clin Pract. 2017 Feb;7(1):86-93
  • 21. Koopman P, Münsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature. 1990 Nov 29;348(6300):450-2
  • 22. Lahr G, Maxson SC, Mayer A, Just W, Pilgrim C, Reisert I. Transcription of the Y chromosomal gene, Sry, in adult mouse brain. Brain Res Mol Brain Res. 1995 Oct;33(1):179-82
  • 23. Mayer A, Lahr G, Swaab DF, Pilgrim C, Reisert I. The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics. 1998 Aug;1(4):281-8
  • 24. Dewing P, Chiang CW, Sinchak K, Sim H, Fernagut PO, Kelly S, Chesselet MF, Micevych PE, Albrecht KH, Harley VR, Vilain E. Direct regulation of adult brain function by the male-specific factor SRY. Curr Biol. 2006 Feb 21;16(4):415-20
  • 25. Di Fonzo A, Rohé CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V; Italian Parkinson Genetics Network. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet. 2005 Jan 29-Feb 4;365(9457):412-5
  • 26. Cookson MR. Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. Cold Spring Harb Perspect Med. 2012 Sep 1;2(9):a009415
  • 27. Okun MS, Crucian GP, Fischer L, Walter BL, Testa CM, Vitek JL, DeLong MR, Hanfelt J, Huang X. Testosterone deficiency in a Parkinson's disease clinic: results of a survey. J Neurol Neurosurg Psychiatry. 2004 Jan;75(1):165-6
  • 28. Mitchell E, Thomas D, Burnet R. Testosterone improves motor function in Parkinson's disease. J Clin Neurosci. 2006 Jan;13(1):133-6
  • 29. Louissaint A Jr, Rao S, Leventhal C, Goldman SA. Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron. 2002 Jun 13;34(6):945-60
  • 30. Chang E, Wang J. Brain-derived neurotrophic factor attenuates cognitive impairment and motor deficits in a mouse model of Parkinson's disease. Brain Behav. 2021 Aug;11(8):e2251
  • 31. Klein RL, Lewis MH, Muzyczka N, Meyer EM. Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer. Brain Res. 1999 Nov 20;847(2):314-20
  • 32. Tsukahara T, Takeda M, Shimohama S, Ohara O, Hashimoto N. Effects of brain-derived neurotrophic factor on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in monkeys. Neurosurgery. 1995 Oct;37(4):733-9; discussion 739-41
There are 32 citations in total.

Details

Primary Language Turkish
Subjects Clinical Sciences, Health Care Administration
Journal Section Research Articles
Authors

Muhammet Ay 0000-0003-1179-593X

Publication Date March 14, 2023
Submission Date August 25, 2022
Acceptance Date November 14, 2022
Published in Issue Year 2023

Cite

Vancouver Ay M. SRY GENİNİN PARKİNSON HASTALIĞINDAKİ POTANSİYEL ROLÜNÜN İN SİLİKO ANALİZİ. Med J SDU. 2023;30(1):19-24.

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