Advertisement

Human Genetics

, Volume 118, Issue 3–4, pp 484–488 | Cite as

Impaired transcriptional upregulation of Parkin promoter variant under oxidative stress and proteasomal inhibition: clinical association

  • E. K. TanEmail author
  • K. Y. Puong
  • D. K. Y. Chan
  • K. Yew
  • S. Fook-Chong
  • H. Shen
  • P. W. Ng
  • J. Woo
  • Y. Yuen
  • R. Pavanni
  • M. C. Wong
  • K. Puvan
  • Y. Zhao
Original Investigation

Abstract

We provided data to show that the transcriptional activity of wildtype −258T in the parkin promoter region was significantly higher than the −258G variant in human cell lines. The transcriptional activity of wildtype −258T was significantly increased under oxidative stress by hydrogen peroxide, but this was not observed for the −258G variant. The transcriptional upregulation was significantly higher for wildtype −258T compared to −258G variant at 0.1, 0.2 and 0.4 mM of hydrogen peroxide. Similar results were obtained when the cells were treated with a proteasome inhibitor, MG132.

Furthermore, in a case control study involving 753 subjects, we demonstrated that the parkin promoter −258G variant was associated with an increased risk of sporadic Parkinson’s disease (PD) in the elderly ethnic Chinese population. Our clinical and laboratory data provide corroborative evidence that some older individuals who have the −258G variant may have a higher risk of developing PD.

Keywords

Parkin Proteasomal Inhibition Transcriptional Upregulation Firefly Luciferase Reporter Aging Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The study was supported by grants from the National Medical Research Council and Department of Clinical Research, Singapore General Hospital. The authors thank the directors of National Neuroscience Institute and SingHealth Research and Dr. AW Swee Eng for his support.

References

  1. Gilks WP, Abou-Sleiman PM, Gandhi S, et al (2005) A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 365(9457):415–416PubMedGoogle Scholar
  2. Hyun DH, Lee M, Hattori N, Kubo S, Mizuno Y, Halliwell B, Jenner P (2002) Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J Biol Chem 9277(32):28572–28577CrossRefGoogle Scholar
  3. Lucking CB, Chesneau V, Lohmann E, et al (2003) Coding polymorphisms in the parkin gene and susceptibility to Parkinson disease. Arch Neurol 60(9):1253–1256PubMedCrossRefGoogle Scholar
  4. Mata IF, Lockhart PJ, Farrer MJ (2004) Parkin genetics: one model for Parkinson’s disease. Hum Mol Genet:1–13Google Scholar
  5. Oliveira SA, Scott WK, Nance MA, et al (2003) Association study of Parkin gene polymorphisms with idiopathic Parkinson disease. Arch Neurol 60(7):975–980PubMedCrossRefGoogle Scholar
  6. Paisan-Ruiz C, Jain S, Evans EW, et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44(4):595–600PubMedCrossRefGoogle Scholar
  7. Pawlyk AC, Giasson BI, Sampathu DM, et al (2003) Novel monoclonal antibodies demonstrate biochemical variation of brain parkin with age. J Biol Chem 278(48):48120–48128PubMedCrossRefGoogle Scholar
  8. Petrucelli L, O’Farrell C, Lockhart PJ, et al (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36(6):1007–1019PubMedCrossRefGoogle Scholar
  9. Tan EK, Khajavi M, Thornby I, Nagamitsu N, Jankovic J, Ashizawa T (2000) Variability and validity of polymorphism association studies in Parkinson’s disease. Neurology 55:533–539PubMedGoogle Scholar
  10. Wang M, Hattori N, Matsumine H, Kobayashi T, Yoshino H, Morioka A, Kitada T, Asakawa S, Minoshima S, Shimizu N, Mizuno Y (1999) Polymorphism in the parkin gene in sporadic Parkinson’s disease. Ann Neurol 45(5):655–658PubMedCrossRefGoogle Scholar
  11. West AB, Maraganore D, Crook J, et al (2002) Functional association of the parkin gene promoter with idiopathic Parkinson’s disease. Hum Mol Genet 11:2787–2792PubMedCrossRefGoogle Scholar
  12. Zimprich A, Biskup S, Leitner P, et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44(4):601–607PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • E. K. Tan
    • 1
    • 4
    • 5
    Email author
  • K. Y. Puong
    • 2
  • D. K. Y. Chan
    • 6
  • K. Yew
    • 1
  • S. Fook-Chong
    • 2
  • H. Shen
    • 1
    • 5
  • P. W. Ng
    • 7
  • J. Woo
    • 8
  • Y. Yuen
    • 3
  • R. Pavanni
    • 1
    • 4
    • 5
  • M. C. Wong
    • 1
    • 4
    • 5
  • K. Puvan
    • 1
    • 4
    • 5
  • Y. Zhao
    • 2
  1. 1.Department of NeurologySingapore General HospitalSingaporeSingapore
  2. 2.Clinical ResearchSingapore General HospitalSingaporeSingapore
  3. 3.Health ScreeningSingapore General HospitalSingaporeSingapore
  4. 4.National Neuroscience InstituteSingaporeSingapore
  5. 5.SingHealth ResearchSingaporeSingapore
  6. 6.Bankstown Lidcome HospitalUniversity of New South WalesSydneyAustralia
  7. 7.United Christian HospitalHong KongChina
  8. 8.Department of Medicine and TherapeuticsChinese University of Hong KongHong KongChina

Personalised recommendations