Journal of Molecular Neuroscience

, Volume 46, Issue 3, pp 541–544 | Cite as

The Age at Motor Symptoms Onset in LRRK2-Associated Parkinson's Disease is Affected by a Variation in the MAPT Locus: A Possible Interaction

  • Ziv Gan-Or
  • Anat Bar-Shira
  • Anat Mirelman
  • Tanya Gurevich
  • Nir Giladi
  • Avi Orr-Urtreger
Article

Abstract

The current paradigm on Parkinson's disease (PD) pathogenesis and course suggests the involvement of multiple genes and the interaction between them. Recently, it was reported that a variation (rs2435207) in the MAPT gene region influenced the age of motor symptoms onset (AO) in 44 PD patients from 19 families, carriers of leucine-rich repeat kinase 2 (LRRK2) mutations, all of European and North American origin. To examine whether genetic factors within the MAPT locus exert a similar effect on AO in a different population of LRRK2-associated PD patients, 99 unrelated Ashkenazi patients with the LRRK2 p.G2019S mutation were analyzed. Three SNPs in the MAPT region were studied, rs393152, rs2435207, and rs11079727; the latter is located in the first intron of MAPT. Among carriers of the single LRRK2 p.G2019S mutation that did not carry a founder Ashkenazi GBA mutation too (n = 84), the AO in minor rs11079727 A allele carriers (C/A genotype) was significantly older (62.5 ± 10.6 years) compared to the AO (55.7 ± 11.6) among carriers of the C/C genotype (p = 0.025). Our results further support a possible interaction between genetic factors in the MAPT region and the LRRK2 gene, which influence the clinical course of PD patients.

Keywords

Parkinson’s disease MAPT Tau LRRK2 

References

  1. Biernacka JM, Armasu SM, Cunningham JM, Eric Ahlskog J, Chung SJ, Maraganore DM (2011) Do interactions between SNCA, MAPT, and LRRK2 genes contribute to Parkinson's disease susceptibility? Parkinsonism Relat Disord. doi:10.1016/j.parkreldis.2011.07.001
  2. Cookson M (2010) The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci 11(12):791–797PubMedCrossRefGoogle Scholar
  3. Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T et al (2008) Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 70:2277–2283PubMedCrossRefGoogle Scholar
  4. Gan-Or Z, Bar-Shira A, Mirelman A, Gurevich T, Kedmi M, Giladi N et al (2010) LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics 11:121–125PubMedCrossRefGoogle Scholar
  5. Gan-Or Z, Bar-Shira A, Gurevich T, Giladi N, Orr-Urtreger A (2011) Homozygosity for the MTX1 c.184T>A (p.S63T) alteration modifies the age at onset in GBA-associated Parkinson’s disease. Neurogenetics. doi:10.1007/s10048-011-0293-6
  6. Giasson BI, Van Deerlin VM (2008) Mutations in LRRK2 as a cause of Parkinson's disease. Neurosignals 16:99–105PubMedCrossRefGoogle Scholar
  7. Golub Y, Berg D, Calne DB, Pfeiffer RF, Uitti RJ, Stoessl AJ et al (2009) Genetic factors influencing age at onset in LRRK2-linked Parkinson disease. Parkinsonism Relat Disord 15:539–541PubMedCrossRefGoogle Scholar
  8. Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case–control study. Lancet Neurol 7(7):583–590PubMedCrossRefGoogle Scholar
  9. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184PubMedCrossRefGoogle Scholar
  10. Melrose HL, Dachsel JC, Behrouz B, Lincoln SJ, Yue M, Hinkle KM et al (2010) Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol Dis 40:503–517PubMedCrossRefGoogle Scholar
  11. Miklossy J, Qing H, Guo JP, Yu S, Wszolek ZK, Calne D et al (2007) Lrrk2 and chronic inflammation are linked to pallido-ponto-nigral degeneration caused by the N279K tau mutation. Acta Neuropathol 114:243–254PubMedCrossRefGoogle Scholar
  12. Orr-Urtreger A, Shifrin C, Rozovski U, Rosner S, Bercovich D, Gurevich T et al (2007) The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect? Neurology 69:1595–1602PubMedCrossRefGoogle Scholar
  13. Rajput A, Dickson DW, Robinson CA, Ross OA, Dachsel JC, Lincoln SJ et al (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67:1506–1508PubMedCrossRefGoogle Scholar
  14. Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D et al (2009) Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet 41:1308–1312PubMedCrossRefGoogle Scholar
  15. Skipper L, Wilkes K, Toft M, Baker M, Lincoln S, Hulihan M et al (2004) Linkage disequilibrium and association of MAPT H1 in Parkinson disease. Am J Hum Genet 75:669–677PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Ziv Gan-Or
    • 1
    • 3
  • Anat Bar-Shira
    • 1
  • Anat Mirelman
    • 2
  • Tanya Gurevich
    • 2
    • 3
  • Nir Giladi
    • 2
    • 3
  • Avi Orr-Urtreger
    • 1
    • 3
  1. 1.The Genetic Institute, Tel-Aviv Sourasky Medical CenterTel AvivIsrael
  2. 2.Movement Disorders Unit, Department of NeurologyTel-Aviv Sourasky Medical CenterTel-AvivIsrael
  3. 3.The Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael

Personalised recommendations