Skip to main content
SpringerLink
Log in

Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk for Parkinson’s disease?

  • Movement Disorders - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

The key symptoms of Parkinson’s disease (PD) are caused by degeneration of dopamine neurons originating in substantia nigra. Whereas, transcription factor LMX1A is crucial for the differentiation of mesencephalic dopamine neurons, LMX1B appears to be important for both the development and the survival of these cells. The aim of this study was to investigate if genetic variation in LMX1A and LMX1B differs between patients with PD (n = 357) and control subjects (n = 1428) by genotyping 33 single nucleotide polymorphisms (SNPs) in LMX1A and 11 SNPs in LMX1B. Three SNPs in LMX1A and one in LMX1B were associated with PD. After splitting for gender, six SNPs were associated with PD in women and four in men. The significances obtained did not survive correction for multiple testing, and our results should hence be interpreted with caution, but are partly in line with a previous report, and should thus be of sufficient interest to encourage further studies of these genes in PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adams KA, Maida JM, Golden JA, Riddle RD (2000) The transcription factor Lmx1b maintains Wnt1 expression within the isthmic organizer. Development 127(9):1857–1867

    PubMed  CAS  Google Scholar 

  • Alavian KN, Scholz C, Simon HH (2008) Transcriptional regulation of mesencephalic dopaminergic neurons: the full circle of life and death. Mov Disord 23(3):319–328

    Article  PubMed  Google Scholar 

  • Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B, Perlmann T, Ericson J (2006) Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124(2):393–405

    Article  PubMed  CAS  Google Scholar 

  • Ang SL (2006) Transcriptional control of midbrain dopaminergic neuron development. Development 133(18):3499–3506

    Article  PubMed  CAS  Google Scholar 

  • Ardayfio P, Moon J, Leung KK, Youn-Hwang D, Kim KS (2008) Impaired learning and memory in Pitx3 deficient aphakia mice: a genetic model for striatum-dependent cognitive symptoms in Parkinson’s disease. Neurobiol Dis 31(3):406–412 [Epub 4 June 2008]

    Article  PubMed  CAS  Google Scholar 

  • Baldereschi M, Di Carlo A, Rocca WA, Vanni P, Maggi S, Perissinotto E, Grigoletto F, Amaducci L, Inzitari D (2000) Parkinson’s disease and parkinsonism in a longitudinal study: two-fold higher incidence in men. ILSA Working Group. Italian Longitudinal Study on Aging. Neurology 55(9):1358–1363

    PubMed  CAS  Google Scholar 

  • Barzilai A, Melamed E (2003) Molecular mechanisms of selective dopaminergic neuronal death in Parkinson’s disease. Trends Mol Med 9(3):126–132

    Article  PubMed  CAS  Google Scholar 

  • Belin AC, Westerlund M (2008) Parkinson’s disease: a genetic perspective. FEBS J 275(7):1377–1383

    Article  PubMed  CAS  Google Scholar 

  • Bergman O, Hakansson A, Westberg L, Nordenstrom K, Carmine Belin A, Sydow O, Olson L, Holmberg B, Eriksson E, Nissbrandt H (2008) PITX3 polymorphism is associated with early onset Parkinson’s disease. Neurobiol Aging. 15 April 2008 [Epub ahead of print]

  • Burbach JP, Smidt MP (2006) Molecular programming of stem cells into mesodiencephalic dopaminergic neurons. Trends Neurosci 29(11):601–603

    Article  PubMed  CAS  Google Scholar 

  • Daniel SE, Lees AJ (1993) Parkinson’s Disease Society Brain Bank, London: overview and research. J Neural Transm Suppl 39:165–172

    PubMed  CAS  Google Scholar 

  • Dunston JA, Hamlington JD, Zaveri J, Sweeney E, Sibbring J, Tran C, Malbroux M, O’Neill JP, Mountford R, McIntosh I (2004) The human LMX1B gene: transcription unit, promoter, and pathogenic mutations. Genomics 84(3):565–576

    Article  PubMed  CAS  Google Scholar 

  • Fratiglioni L, Viitanen M, Backman L, Sandman PO, Winblad B (1992) Occurrence of dementia in advanced age: the study design of the Kungsholmen Project. Neuroepidemiology 11(Suppl 1):29–36

    Article  PubMed  Google Scholar 

  • Fuchs J, Mueller JC, Lichtner P, Schulte C, Munz M, Berg D, Wullner U, Illig T, Sharma M, Gasser T (2007) The transcription factor PITX3 is associated with sporadic Parkinson’s disease. Neurobiol Aging. 28 September 2007 [Epub ahead of print]

  • Fung HC, Scholz S, Matarin M, Simon-Sanchez J, Hernandez D, Britton A, Gibbs JR, Langefeld C, Stiegert ML, Schymick J, Okun MS, Mandel RJ, Fernandez HH, Foote KD, Rodriguez RL, Peckham E, De Vrieze FW, Gwinn-Hardy K, Hardy JA, Singleton A (2006) Genome-wide genotyping in Parkinson’s disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 5(11):911–916

    Article  PubMed  CAS  Google Scholar 

  • Gasser T (2005) Genetics of Parkinson’s disease. Curr Opin Neurol 18(4):363–369

    Article  PubMed  CAS  Google Scholar 

  • Hicks AA, Petursson H, Jonsson T, Stefansson H, Johannsdottir HS, Sainz J, Frigge ML, Kong A, Gulcher JR, Stefansson K, Sveinbjornsdottir S (2002) A susceptibility gene for late-onset idiopathic Parkinson’s disease. Ann Neurol 52(5):549–555

    Article  PubMed  CAS  Google Scholar 

  • Kleinjan DA, van Heyningen V (2005) Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet 76(1):8–32

    Article  PubMed  CAS  Google Scholar 

  • Kuppers E, Ivanova T, Karolczak M, Beyer C (2000) Estrogen: a multifunctional messenger to nigrostriatal dopaminergic neurons. J Neurocytol 29(5–6):375–385

    Article  PubMed  CAS  Google Scholar 

  • Manthey D, Behl C (2006) From structural biochemistry to expression profiling: neuroprotective activities of estrogen. Neuroscience 138(3):845–850

    Article  PubMed  CAS  Google Scholar 

  • Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, Rocca WA, Pant PV, Frazer KA, Cox DR, Ballinger DG (2005) High-resolution whole-genome association study of Parkinson disease. Am J Hum Genet 77(5):685–693

    Article  PubMed  CAS  Google Scholar 

  • Ono Y, Nakatani T, Sakamoto Y, Mizuhara E, Minaki Y, Kumai M, Hamaguchi A, Nishimura M, Inoue Y, Hayashi H, Takahashi J, Imai T (2007) Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells. Development 134(17):3213–3225

    Article  PubMed  CAS  Google Scholar 

  • Roybon L, Hjalt T, Christophersen NS, Li JY, Brundin P (2008) Effects on differentiation of embryonic ventral midbrain progenitors by Lmx1a, MSX1, Ngn2, and Pitx3. J Neurosci 28(14):3644–3656

    Article  PubMed  CAS  Google Scholar 

  • Scherzer CR, Grass JA, Liao Z, Pepivani I, Zheng B, Eklund AC, Ney PA, Ng J, McGoldrick M, Mollenhauer B, Bresnick EH, Schlossmacher MG (2008) GATA transcription factors directly regulate the Parkinson’s disease-linked gene {alpha}-synuclein. Proc Natl Acad Sci USA 105:10907–10912 [Epub 31 July 2008]

    Article  PubMed  CAS  Google Scholar 

  • Smidt MP, Burbach JP (2007) How to make a mesodiencephalic dopaminergic neuron. Nat Rev Neurosci 8(1):21–32

    Article  PubMed  CAS  Google Scholar 

  • Smidt MP, Asbreuk CH, Cox JJ, Chen H, Johnson RL, Burbach JP (2000) A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 3(4):337–341

    Article  PubMed  CAS  Google Scholar 

  • Sutherland G, Mellick G, Sue C, Chan DK, Rowe D, Silburn P, Halliday G (2007) A functional polymorphism in the parkin gene promoter affects the age of onset of Parkinson’s disease. Neurosci Lett 414(2):170–173

    Article  PubMed  CAS  Google Scholar 

  • Thameem F, Wolford JK, Wang J, German MS, Bogardus C, Prochazka M (2002) Cloning, expression and genomic structure of human LMX1A, and variant screening in Pima Indians. Gene 290(1–2):217–225

    Article  PubMed  CAS  Google Scholar 

  • Tokuhiro S, Yamada R, Chang X, Suzuki A, Kochi Y, Sawada T, Suzuki M, Nagasaki M, Ohtsuki M, Ono M, Furukawa H, Nagashima M, Yoshino S, Mabuchi A, Sekine A, Saito S, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat Genet 35(4):341–348

    Article  PubMed  CAS  Google Scholar 

  • Wallen A, Perlmann T (2003) Transcriptional control of dopamine neuron development. Ann N Y Acad Sci 991:48–60

    Article  PubMed  CAS  Google Scholar 

  • Westberg L, Hakansson A, Melke J, Shahabi HN, Nilsson S, Buervenich S, Carmine A, Ahlberg J, Grundell MB, Schulhof B, Klingborg K, Holmberg B, Sydow O, Olson L, Johnels EB, Eriksson E, Nissbrandt H (2004) Association between the estrogen receptor beta gene and age of onset of Parkinson’s disease. Psychoneuroendocrinology 29(8):993–998

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Ann-Christin Thelander, Gunilla Bourghardt and Inger Oscarsson for technical assistance and Staffan Nilsson and Susanne Henningsson for statistical advice. Swedish Brain Power, the Swedish Research Council, the Swedish Parkinson foundation, the Swedish Brain foundation, the Royal Society of Arts and Sciences in Göteborg, Adlerbert research foundation, Åhlén foundation and Karolinska Institutet funds, sponsored the study.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, P.O.B. 431, 40530, Gothenburg, Sweden

    Olle Bergman, Anna Håkansson, Lars Westberg, Elias Eriksson & Hans Nissbrandt

  2. Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

    Björn Holmberg

  3. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Andrea Carmine Belin & Lars Olson

  4. Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Olof Sydow

  5. The Aging Research Center, Karolinska Institutet, Stockholm, Sweden

    Laura Fratiglioni & Lars Bäckman

Authors
  1. Olle Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna Håkansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lars Westberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andrea Carmine Belin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Olof Sydow
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Björn Holmberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laura Fratiglioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lars Bäckman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Elias Eriksson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hans Nissbrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Olle Bergman.

Additional information

O. Bergman and A. Håkansson contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bergman, O., Håkansson, A., Westberg, L. et al. Do polymorphisms in transcription factors LMX1A and LMX1B influence the risk for Parkinson’s disease?. J Neural Transm 116, 333–338 (2009). https://doi.org/10.1007/s00702-009-0187-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-009-0187-z

Keywords

Search

Navigation