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Vol. 5, No. 3-4, 2008
Issue release date: March 2008
Free Access
Neurodegenerative Dis 2008;5:222–224
(DOI:10.1159/000113708)

Leucine-Rich Repeat Kinase 2 Colocalizes with α-Synuclein in Parkinson’s Disease, but Not Tau-Containing Deposits in Tauopathies

Perry G.a, b · Zhu X.a · Babar A.K.a · Siedlak S.L.a · Yang Q.a · Ito G.c · Iwatsubo T.c · Smith M.A.a · Chen S.G.a
aDepartment of Pathology, Case Western Reserve University, Cleveland, Ohio, and bCollege of Sciences, The University of Texas at San Antonio, San Antonio, Tex., USA; cDepartment of Neuropathology and Neuroscience, University of Tokyo, Tokyo, Japan
email Corresponding Author

Abstract

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.


 goto top of outline Key Words

  • Lewy bodies
  • Leucine-rich repeat kinase 2
  • Parkinson’s disease
  • Synuclein

 goto top of outline Abstract

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


 goto top of outline References
  1. Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A: Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 2006;60:389–398.
  2. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature 1997;388:839–840.
  3. 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.

    External Resources

  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Iwatsubo T: Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 2003;250(suppl 3):III11–III14.

 goto top of outline Author Contacts

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 george.perry@utsa.edu


 goto top of outline Article Information

Published online: March 6, 2008
Number of Print Pages : 3
Number of Figures : 1, Number of Tables : 0, Number of References : 10


 goto top of outline Publication Details

Neurodegenerative Diseases

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


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

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.



 goto top of outline Author Contacts

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 george.perry@utsa.edu


 goto top of outline Article Information

Published online: March 6, 2008
Number of Print Pages : 3
Number of Figures : 1, Number of Tables : 0, Number of References : 10


 goto top of outline Publication Details

Neurodegenerative Diseases

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


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A: Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 2006;60:389–398.
  2. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M: Alpha-synuclein in Lewy bodies. Nature 1997;388:839–840.
  3. 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.

    External Resources

  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Iwatsubo T: Aggregation of alpha-synuclein in the pathogenesis of Parkinson’s disease. J Neurol 2003;250(suppl 3):III11–III14.