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Vol. 7, No. 1-3, 2010
Issue release date: April 2010
Free Access
Neurodegenerative Dis 2010;7:175–179
(DOI:10.1159/000289232)

Leucine-Rich Repeat Kinase 2 Gene-Associated Disease: Redefining Genotype-Phenotype Correlation

Wider C.a · Dickson D.W.b · Wszolek Z.K.a
Departments of aNeurology, and bNeuropathology, Mayo Clinic, Jacksonville, Fla., USA
email Corresponding Author

Abstract

Background: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson’s disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. Methods: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. Results: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was ‘pure’ nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, α-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. Conclusions: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or ‘pure’ nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity.


 goto top of outline Key Words

  • Leucine-rich repeat kinase 2gene
  • Parkinson’s disease
  • Lewy body disease
  • Progressive supranuclear gaze palsy
  • Nigral degeneration

 goto top of outline Abstract

Background: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson’s disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. Methods: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. Results: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was ‘pure’ nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, α-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. Conclusions: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or ‘pure’ nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity.

Copyright © 2010 S. Karger AG, Basel


 goto top of outline References
  1. Farrer MJ: Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 2006;7:306–318.
  2. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601–607.
  3. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimprich A, Muller-Myhsok B, Farrer MJ, Gasser T, Calne DB, Dickson DW: Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004;62:1619–1622.
  4. Ross OA, Toft M, Haugarvoll K: Corticobasal syndrome and primary progressive aphasia as manifestations of lrrk2 gene mutations. Neurology 2008;71:303; author reply 303–304.
  5. Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW: Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583–590.
  6. Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohe CF, Chang HC, Chen RS, Weng YH, Vanacore N, Breedveld GJ, Oostra BA, Bonifati V: A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics 2006;7:133–138.
  7. Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM: Analysis of Lrrk2 R1628P as a risk factor for Parkinson’s disease. Ann Neurol 2008;64:88–92.
  8. Wszolek ZK, Pfeiffer B, Fulgham JR, Parisi JE, Thompson BM, Uitti RJ, Calne DB, Pfeiffer RF: Western Nebraska family (family D) with autosomal dominant parkinsonism. Neurology 1995;45:502–505.
  9. Wszolek ZK, Vieregge P, Uitti RJ, Gasser T, Yasuhara O, McGeer P, Berry K, Calne DB, Vingerhoets FJ, Klein C, Pfeiffer RF: German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia – longitudinal observations. Parkinsonism Relat Disord 1997;3:125–139.
  10. Chen-Plotkin AS, Yuan W, Anderson C, McCarty Wood E, Hurtig HI, Clark CM, Miller BL, Lee VM, Trojanowski JQ, Grossman M, Van Deerlin VM: Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations. Neurology 2008;70:521–527.
  11. Spanaki C, Latsoudis H, Plaitakis A: LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP. Neurology 2006;67:1518–1519.
  12. Dachsel JC, Ross OA, Mata IF, Kachergus J, Toft M, Cannon A, Baker M, Adamson J, Hutton M, Dickson DW, Farrer MJ: Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol 2007;113:601–606.
  13. Rajput A, Dickson DW, Robinson CA, Ross OA, Dachsel JC, Lincoln SJ, Cobb SA, Rajput ML, Farrer MJ: Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 2006;67:1506–1508.
  14. Gaig C, Ezquerra M, Marti MJ, Valldeoriola F, Munoz E, Llado A, Rey MJ, Cardozo A, Molinuevo JL, Tolosa E: Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration. J Neurol Sci 2008;270:94–98.
  15. Gaig C, Marti MJ, Ezquerra M, Rey MJ, Cardozo A, Tolosa E: G2019S LRRK2 mutation causing Parkinson’s disease without Lewy bodies. J Neurol Neurosurg Psychiatry 2007;78:626–628.
  16. Hasegawa K, Stoessl AJ, Yokoyama T, Kowa H, Wszolek ZK, Yagishita S: Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism Relat Disord 2009;15:300–306.
  17. 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.
  18. Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW: A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005;365:415–416.
  19. Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW: Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388–393.
  20. Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW: Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005;128:2786–2796.
  21. Santpere G, Ferrer I: LRRK2 and neurodegeneration. Acta Neuropathol 2009;117:227–246.
  22. Devine MJ, Lewis PA: Emerging pathways in genetic Parkinson’s disease: tangles, Lewy bodies and LRRK2. FEBS J 2008;275:5748–5757.
  23. Melrose HL, Kent CB, Taylor JP, Dachsel JC, Hinkle KM, Lincoln SJ, Mok SS, Culvenor JG, Masters CL, Tyndall GM, Bass DI, Ahmed Z, Andorfer CA, Ross OA, Wszolek ZK, Delldonne A, Dickson DW, Farrer MJ: A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease. Neuroscience 2007;147:1047–1058.
  24. West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim KL, Dawson VL, Dawson TM: Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 2007;16:223–232.
  25. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR: LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem J 2007;405:307–317.

 goto top of outline Author Contacts

Zbigniew K. Wszolek, MD
Neurology, Cannaday 2E
Mayo Clinic, 4500 San Pablo Road
Jacksonville, FL 32224 (USA)
Tel. +1 904 953 7229, Fax +1 904 953 0757, E-Mail wszolek.zbigniew@mayo.edu


 goto top of outline Article Information

Published online: March 3, 2010
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 1, Number of References : 25


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 7, No. 1-3, Year 2010 (Cover Date: April 2010)

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: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson’s disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. Methods: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. Results: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was ‘pure’ nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, α-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. Conclusions: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or ‘pure’ nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity.



 goto top of outline Author Contacts

Zbigniew K. Wszolek, MD
Neurology, Cannaday 2E
Mayo Clinic, 4500 San Pablo Road
Jacksonville, FL 32224 (USA)
Tel. +1 904 953 7229, Fax +1 904 953 0757, E-Mail wszolek.zbigniew@mayo.edu


 goto top of outline Article Information

Published online: March 3, 2010
Number of Print Pages : 5
Number of Figures : 1, Number of Tables : 1, Number of References : 25


 goto top of outline Publication Details

Neurodegenerative Diseases

Vol. 7, No. 1-3, Year 2010 (Cover Date: April 2010)

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. Farrer MJ: Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 2006;7:306–318.
  2. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601–607.
  3. Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimprich A, Muller-Myhsok B, Farrer MJ, Gasser T, Calne DB, Dickson DW: Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004;62:1619–1622.
  4. Ross OA, Toft M, Haugarvoll K: Corticobasal syndrome and primary progressive aphasia as manifestations of lrrk2 gene mutations. Neurology 2008;71:303; author reply 303–304.
  5. Healy DG, Falchi M, O’Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW: Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol 2008;7:583–590.
  6. Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohe CF, Chang HC, Chen RS, Weng YH, Vanacore N, Breedveld GJ, Oostra BA, Bonifati V: A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson’s disease risk in Taiwan. Neurogenetics 2006;7:133–138.
  7. Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, Mata IF, Lee-Chen GJ, Chen CM, Tang M, Zhao Y, Hattori N, Farrer MJ, Tan EK, Wu RM: Analysis of Lrrk2 R1628P as a risk factor for Parkinson’s disease. Ann Neurol 2008;64:88–92.
  8. Wszolek ZK, Pfeiffer B, Fulgham JR, Parisi JE, Thompson BM, Uitti RJ, Calne DB, Pfeiffer RF: Western Nebraska family (family D) with autosomal dominant parkinsonism. Neurology 1995;45:502–505.
  9. Wszolek ZK, Vieregge P, Uitti RJ, Gasser T, Yasuhara O, McGeer P, Berry K, Calne DB, Vingerhoets FJ, Klein C, Pfeiffer RF: German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia – longitudinal observations. Parkinsonism Relat Disord 1997;3:125–139.
  10. Chen-Plotkin AS, Yuan W, Anderson C, McCarty Wood E, Hurtig HI, Clark CM, Miller BL, Lee VM, Trojanowski JQ, Grossman M, Van Deerlin VM: Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations. Neurology 2008;70:521–527.
  11. Spanaki C, Latsoudis H, Plaitakis A: LRRK2 mutations on Crete: R1441H associated with PD evolving to PSP. Neurology 2006;67:1518–1519.
  12. Dachsel JC, Ross OA, Mata IF, Kachergus J, Toft M, Cannon A, Baker M, Adamson J, Hutton M, Dickson DW, Farrer MJ: Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathol 2007;113:601–606.
  13. Rajput A, Dickson DW, Robinson CA, Ross OA, Dachsel JC, Lincoln SJ, Cobb SA, Rajput ML, Farrer MJ: Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 2006;67:1506–1508.
  14. Gaig C, Ezquerra M, Marti MJ, Valldeoriola F, Munoz E, Llado A, Rey MJ, Cardozo A, Molinuevo JL, Tolosa E: Screening for the LRRK2 G2019S and codon-1441 mutations in a pathological series of parkinsonian syndromes and frontotemporal lobar degeneration. J Neurol Sci 2008;270:94–98.
  15. Gaig C, Marti MJ, Ezquerra M, Rey MJ, Cardozo A, Tolosa E: G2019S LRRK2 mutation causing Parkinson’s disease without Lewy bodies. J Neurol Neurosurg Psychiatry 2007;78:626–628.
  16. Hasegawa K, Stoessl AJ, Yokoyama T, Kowa H, Wszolek ZK, Yagishita S: Familial parkinsonism: study of original Sagamihara PARK8 (I2020T) kindred with variable clinicopathologic outcomes. Parkinsonism Relat Disord 2009;15:300–306.
  17. 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.
  18. Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW: A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 2005;365:415–416.
  19. Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC, Litvan I, Gordon MF, Wszolek ZK, Farrer MJ, Dickson DW: Lrrk2 and Lewy body disease. Ann Neurol 2006;59:388–393.
  20. Khan NL, Jain S, Lynch JM, Pavese N, Abou-Sleiman P, Holton JL, Healy DG, Gilks WP, Sweeney MG, Ganguly M, Gibbons V, Gandhi S, Vaughan J, Eunson LH, Katzenschlager R, Gayton J, Lennox G, Revesz T, Nicholl D, Bhatia KP, Quinn N, Brooks D, Lees AJ, Davis MB, Piccini P, Singleton AB, Wood NW: Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005;128:2786–2796.
  21. Santpere G, Ferrer I: LRRK2 and neurodegeneration. Acta Neuropathol 2009;117:227–246.
  22. Devine MJ, Lewis PA: Emerging pathways in genetic Parkinson’s disease: tangles, Lewy bodies and LRRK2. FEBS J 2008;275:5748–5757.
  23. Melrose HL, Kent CB, Taylor JP, Dachsel JC, Hinkle KM, Lincoln SJ, Mok SS, Culvenor JG, Masters CL, Tyndall GM, Bass DI, Ahmed Z, Andorfer CA, Ross OA, Wszolek ZK, Delldonne A, Dickson DW, Farrer MJ: A comparative analysis of leucine-rich repeat kinase 2 (Lrrk2) expression in mouse brain and Lewy body disease. Neuroscience 2007;147:1047–1058.
  24. West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim KL, Dawson VL, Dawson TM: Parkinson’s disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet 2007;16:223–232.
  25. Jaleel M, Nichols RJ, Deak M, Campbell DG, Gillardon F, Knebel A, Alessi DR: LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson’s disease mutants affect kinase activity. Biochem J 2007;405:307–317.