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LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease

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Abstract

GBA and LRRK2 mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the LRRK2 G2019S and for eight GBA mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of GBA mutations, carriers of LRRK2 G2019S mutation, and non-carriers. More LRRK2 G2019S carriers reported muscle stiffness (rigidity, p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness (bradykinesia, p = 0.021). These results suggest distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD.

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References

  1. Healy DG, Falchi M, O’Sullivan SS et al (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 7:583–590. doi:10.1016/S1474-4422(08)70117-0

    Article  CAS  PubMed  Google Scholar 

  2. Rogaeva E, Hardy J (2008) Gaucher and Parkinson diseases: unexpectedly related. Neurology 70:2272–2273. doi:10.1212/01.wnl.0000314657.92762.0f

    Article  PubMed  Google Scholar 

  3. Ozelius LJ, Senthil G, Saunders-Pullman R et al (2006) LRRK2 G2019S as a cause of Parkinson’s disease in Ashkenazi Jews. N Engl J Med 354:424–425. doi:10.1056/NEJMc055509

    Article  CAS  PubMed  Google Scholar 

  4. Clark LN, Ross BM, Wang Y et al (2007) Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 69:1270–1277. doi:10.1212/01.wnl.0000276989.17578.02

    Article  CAS  PubMed  Google Scholar 

  5. Gan-Or Z, Giladi N, Rozovski U et al (2008) Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 70:2277–2283. doi:10.1212/01.wnl.0000304039.11891.29

    Article  CAS  PubMed  Google Scholar 

  6. Orr-Urtreger A, Shifrin C, Rozovski U et al (2007) The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: is there a gender effect? Neurology 69:1595–1602. doi:10.1212/01.wnl.0000277637.33328.d8

    Article  CAS  PubMed  Google Scholar 

  7. Beutler E, Gelbart T, Scott CR (2005) Hematologically important mutations: Gaucher disease. Blood Cells Mol Dis 35:355–364. doi:10.1016/j.bcmd.2005.07.005

    Article  CAS  PubMed  Google Scholar 

  8. Moore DJ (2008) The biology and pathobiology of LRRK2: implications for Parkinson’s disease. Parkinsonism Relat Disord 14(Suppl 2):S92–S98. doi:10.1016/j.parkreldis.2008.04.010

    Article  PubMed  Google Scholar 

  9. Lesage S, Belarbi S, Troiano A et al (2008) Is the common LRRK2 G2019S mutation related to dyskinesias in North African Parkinson disease? Neurology 71:1550–1552. doi:10.1212/01.wnl.0000338460.89796.06

    Article  CAS  PubMed  Google Scholar 

  10. Uitti RJ, Baba Y, Wszolek ZK et al (2005) Defining the Parkinson’s disease phenotype: initial symptoms and baseline characteristics in a clinical cohort. Parkinsonism Relat Disord 11:139–145. doi:10.1016/j.parkreldis.2004.10.007

    Article  PubMed  Google Scholar 

  11. Roos RA, Jongen JC, van der Velde EA (1996) Clinical course of patients with idiopathic Parkinson’s disease. Mov Disord 11:236–242. doi:10.1002/mds.870110304

    Article  CAS  PubMed  Google Scholar 

  12. Djaldetti R, Hassin-Baer S, Farrer MJ et al (2008) Clinical characteristics of Parkinson’s disease among Jewish Ethnic groups in Israel. J Neural Transm 115:1279–1284. doi:10.1007/s00702-008-0074-z

    Article  CAS  PubMed  Google Scholar 

  13. Papapetropoulos S, Adi N, Ellul J et al (2007) A prospective study of familial versus sporadic Parkinson’s disease. Neurodegener Dis 4:424–427. doi:10.1159/000107702

    Article  PubMed  Google Scholar 

  14. Papapetropoulos S, Paschalis C, Athanassiadou A et al (2001) Clinical phenotype in patients with alpha-synuclein Parkinson’s disease living in Greece in comparison with patients with sporadic Parkinson’s disease. J Neurol Neurosurg Psychiatry 70:662–665. doi:10.1136/jnnp. 70.5.662

    Article  CAS  PubMed  Google Scholar 

  15. Devine MJ, Lewis PA (2008) Emerging pathways in genetic Parkinson’s disease: tangles, Lewy bodies and LRRK2. FEBS J 275:5748–5757. doi:10.1111/j.1742-4658.2008.06707.x

    Article  CAS  PubMed  Google Scholar 

  16. Ho CC, Rideout HJ, Ribe E et al (2009) The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration. J Neurosci 29:1011–1016. doi:10.1523/JNEUROSCI.5175-08.2009

    Article  CAS  PubMed  Google Scholar 

  17. Liou AK, Leak RK, Li L et al (2008) Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway. Neurobiol Dis 32:116–124. doi:10.1016/j.nbd.2008.06.016

    Article  CAS  PubMed  Google Scholar 

  18. Ron I, Horowitz M (2005) ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity. Hum Mol Genet 14:2387–2398. doi:10.1093/hmg/ddi240

    Article  CAS  PubMed  Google Scholar 

  19. Cuervo AM, Stefanis L, Fredenburg R et al (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295. doi:10.1126/science.1101738

    Article  CAS  PubMed  Google Scholar 

  20. Bras J, Singleton A, Cookson MR et al (2008) Emerging pathways in genetic Parkinson’s disease: potential role of ceramide metabolism in Lewy body disease. FEBS J 275:5767–5773. doi:10.1111/j.1742-4658.2008.06709.x

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from National Parkinson Foundation, Miami, FL, USA, the Tel Aviv Sourasky Medical Center Grant of Excellence and the Wolfson and Kahn Foundations. The assistance of Ilana Elroi, Shiran Levi, Chen Shifrin, and Orna Moore is acknowledged. The authors report no conflicts of interests.

This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Ziv Gan-Or, Sackler Faculty of Medicine, Tel Aviv University, Israel.

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The experiments presented herein comply with the current laws of Israel, the country in which they were performed.

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Correspondence to A. Orr-Urtreger.

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Gan-Or, Z., Bar-Shira, A., Mirelman, A. et al. LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease. Neurogenetics 11, 121–125 (2010). https://doi.org/10.1007/s10048-009-0198-9

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  • DOI: https://doi.org/10.1007/s10048-009-0198-9

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