- Lewy bodies
- Leucine-rich repeat kinase 2
- Parkinson’s disease
Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson’s disease. Objective:To examine whether LRRK2 is directly associated with the pathological structures of Parkinson’s disease, dementia with Lewy bodies, and other related disorders using highly specific antibodies to LRRK2. Results:LRRK2 antibodies strongly labeled brainstem and cortical Lewy bodies, the pathological hallmarks of Parkinson’s disease and dementia with Lewy bodies, respectively. We found that 20–100% (mean 60%) of α-synuclein-positive Lewy bodies contained LRRK2. While antibodies raised against various regions of LRRK2 were previously shown to label recombinant LRRK2 on Western blots, only antibodies raised against the N- and C-termini, but not the regions containing folded protein domains of LRRK2, immunolabeled Lewy bodies. In Alzheimer’s disease, Hirano bodies were found to contain LRRK2 and the neurofibrillary tangles in progressive supranuclear palsy remained unlabeled. Conclusions: Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of Parkinson’s disease and related disorders.
Copyright © 2008 S. Karger AG, Basel
- Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A: Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 2006;60:389–398.
- Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature 1997;388:839–840.
- Zhu X, Babar A, Siedlak SL, Yang Q, Ito G, Iwatsubo T, Smith MA, Perry G, Chen SG: LRRK2 in Parkinson’s disease and dementia with Lewy bodies. Mol Neurodegener 2006;1:17.
- Zhu X, Siedlak SL, Smith MA, Perry G, Chen SG: LRRK2 protein is a component of Lewy bodies. Ann Neurol 2006;60:617–618; author reply 618–619.
- Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, Van Deerlin VM: Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006;59:315–322.
- Greggio E, Jain S, Kingsbury A, Bandopadhyay R, Lewis P, Kaganovich A, van der Brug MP, Beilina A, Blackinton J, Thomas KJ, Ahmad R, Miller DW, Kesavapany S, Singleton A, Lees A, Harvey RJ, Harvey K, Cookson MR: Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiol Dis 2006;23:329–341.
- Miklossy J, Arai T, Guo JP, Klegeris A, Yu S, McGeer EG, McGeer PL: LRRK2 expression in normal and pathologic human brain and in human cell lines. J Neuropathol Exp Neurol 2006;65:953–963.
- Hatano T, Kubo SI, Imai S, Maeda M, Ishikawa K, Mizuno Y, Hattori N: Leucine-rich repeat kinase 2 associates with lipid rafts. Hum Mol Genet 2007;16:678–690.
- West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM: Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 2005;102:16842–16847.
- Iwatsubo T: Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 2003;250(suppl 3):III11–III14.
George Perry, PhD
College of Sciences, University of Texas at San Antonio
One USTA Circle
San Antonio, TX 78249 (USA)
Tel. +1 210 458 4450, Fax +1 210 458 4445, E-Mail firstname.lastname@example.org
Published online: March 6, 2008
Number of Print Pages : 3
Number of Figures : 1, Number of Tables : 0, Number of References : 10
Vol. 5, No. 3-4, Year 2008 (Cover Date: March 2008)
Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660–2854 (Print), eISSN: 1660–2862 (Online)
For additional information: http://www.karger.com/NDD
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