Tau and α-synuclein in susceptibility to, and dementia in, Parkinson's disease
Corresponding Author
An Goris PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
Laboratory for Neuroimmunology, Section for Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Laboratory for Neuroimmunology, K. U. Leuven, Herestraat 49, O&N2, Box 1022, 3000 Leuven, BelgiumSearch for more papers by this authorCaroline H. Williams-Gray MRCP
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Search for more papers by this authorGraeme R. Clark MSc
Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorThomas Foltynie PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorSimon J. G. Lewis PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorJoanne Brown BA(Hons)
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorMaria Ban PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorMaria G. Spillantini PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorAlastair Compston PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorDavid J. Burn PhD
Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorPatrick F. Chinnery PhD
Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorRoger A. Barker PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Search for more papers by this authorStephen J. Sawcer PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Search for more papers by this authorCorresponding Author
An Goris PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
Laboratory for Neuroimmunology, Section for Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Laboratory for Neuroimmunology, K. U. Leuven, Herestraat 49, O&N2, Box 1022, 3000 Leuven, BelgiumSearch for more papers by this authorCaroline H. Williams-Gray MRCP
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Search for more papers by this authorGraeme R. Clark MSc
Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorThomas Foltynie PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorSimon J. G. Lewis PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorJoanne Brown BA(Hons)
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorMaria Ban PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorMaria G. Spillantini PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorAlastair Compston PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorDavid J. Burn PhD
Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorPatrick F. Chinnery PhD
Department of Neurology, School of Neurology, Neurobiology, and Psychiatry, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
Search for more papers by this authorRoger A. Barker PhD
Department of Clinical Neurosciences (Cambridge Centre for Brain Repair), University of Cambridge, Cambridge, United Kingdom
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Search for more papers by this authorStephen J. Sawcer PhD
Department of Clinical Neurosciences (Neurology Unit), University of Cambridge, Cambridge, United Kingdom
A.G. and C.H.W.-G. are joint first authors, and R.A.B. and S.J.S. are joint senior authors.
Search for more papers by this authorAbstract
Objective
Parkinson's disease (PD) is a neurodegenerative condition that typically presents as a movement disorder but is known to be associated with variable degrees of cognitive impairment including dementia. We investigated the genetic basis of susceptibility to and cognitive heterogeneity of this disease.
Methods
In 659 PD patients, 109 of which were followed up for 3.5 years from diagnosis, and 2,176 control subjects, we studied candidate genes involved in protein aggregation and inclusion body formation, the pathological hallmark of parkinsonism: microtubule-associated protein tau (MAPT), glycogen synthase kinase-3β (GSK3B), and α-synuclein (SNCA).
Results
We observed that cognitive decline and the development of PD dementia are strongly associated (p = 10−4) with the inversion polymorphism containing MAPT. We also found a novel synergistic interaction between the MAPT inversion polymorphism and the single nucleotide polymorphism rs356219 from the 3′ region of SNCA. In our data, carrying a risk genotype at either of these loci marginally increases the risk for development of PD, whereas carrying the combination of risk genotypes at both loci approximately doubles the risk for development of the disease (p = 3 × 10−6).
Interpretation
Our data support the hypothesis that tau and α-synuclein are involved in shared or converging pathways in the pathogenesis of PD, and suggest that the tau inversion influences the development of cognitive impairment and dementia in patients with idiopathic PD. These findings have potentially important implications for understanding the interface between tau and α-synuclein pathways in neurodegenerative disorders and for unraveling the biological basis for cognitive impairment and dementia in PD. Ann Neurol 2007
Supporting Information
This article includes supplementary materials available via the Internet at http://www.interscience.wiley.com/jpages/0364-5134/suppmat
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References
- 1 Jain S, Wood NW, Healy DG. Molecular genetic pathways in Parkinson's disease: a review. Clin Sci (Lond) 2005; 109: 355–364.
- 2 Maraganore DM, de Andrade M, Lesnick TG, et al. High-resolution whole-genome association study of Parkinson's disease. Am J Hum Genet 2005; 77: 685–693.
- 3 Clarimon J, Scholz S, Fung H-C, et al. Conflicting results regarding thesemaphorin gene (SEMA5A) and the risk for Parkinson disease. Am J Hum Genet 2006; 78: 1082–1084.
- 4 Farrer MJ, Haugarvoll K, Ross OA, et al. Genome-wide association, Parkinson disease and PARK10. Am J Hum Genet 2006; 78: 1084–1088.
- 5 Goris A, Williams-Gray CH, Foltynie T, et al. No evidence for association with Parkinson disease for 13 single-nucleotide polymorphisms identified by whole-genome association screening. Am J Hum Genet 2006; 78: 1088–1090.
- 6 Li Y, Rowland C, Schrodi S, et al. A case-control study of the 12 single-nucleotide polymorphisms implicated in Parkinson disease by a recent genome scan. Am J Hum Genet 2006; 78: 1090–1092.
- 7 Elbaz A, Nelson LM, Payami H, et al. Lack of replication of thirteen single-nucleotide polymorphisms implicated in Parkinson's disease: a large-scale international study. Lancet Neurol 2006; 5: 917–923.
- 8 Emre M. Dementia associated with Parkinson's disease. Lancet Neurol 2003; 2: 229–237.
- 9 Galpern WR, Lang AE. Interface between tauopathies and synucleinopathies: a tale of two proteins. Ann Neurol 2006; 59: 449–458.
- 10 Kwok JB, Hallupp M, Loy CT, et al. GSK3B polymorphisms alter transcription and splicing in Parkinson's disease. Ann Neurol 2005; 58: 829–839.
- 11 Williams-Gray CH, Goris A, Foltynie T, et al. Prevalence of the LRRK2 G2019S mutation in a UK community based idiopathic Parkinson's disease cohort. J Neurol Neurosurg Psychiatry 2006; 77: 665–667.
- 12 Goris A, Maranian M, Walton A, et al. No evidence for association of a European-specific chromosome 17 inversion with multiple sclerosis. Eur J Hum Genet 2006; 14: 1064.
- 13 The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447: 661–678.
- 14 Foltynie T, Brayne CE, Robbins TW, et al. The cognitive ability of an incident cohort of Parkinson's patients in the UK. The CamPaIGN study. Brain 2004; 127: 550–560.
- 15 Stefansson H, Helgason A, Thorleifsson G, et al. A common inversion under selection in Europeans. Nat Genet 2005; 37: 129–137.
- 16 Dudbridge F. Pedigree disequilibrium tests for multilocus haplotypes. Genet Epidemiol 2003; 25: 115–121.
- 17 Healy DG, Abou-Sleiman PM, Lees AJ, et al. Tau gene and Parkinson's disease: a case-control study and meta-analysis. J Neurol Neurosurg Psychiatry 2004; 75: 962–965.
- 18 Skipper L, Wilkes K, Toft M, et al. Linkage disequilibrium and association of MAPT H1 in Parkinson disease. Am J Hum Genet 2004; 75: 669–677.
- 19 Levecque C, Elbaz A, Clavel J, et al. Association of polymorphisms in the Tau and Saitohin genes with Parkinson's disease. J Neurol Neurosurg Psychiatry 2004; 75: 478–480.
- 20 Mamah CE, Lesnick TG, Lincoln SJ, et al. Interaction of alpha-synuclein and tau genotypes in Parkinson's disease. Ann Neurol 2005; 57: 439–443.
- 21 Zabetian CP, Hutter CM, Factor SA, et al. Association analysis of MAPT H1 haplotype and subhaplotypes in Parkinson's disease. Ann Neurol (in press).
- 22 Peplonska B, Zekanowski C, Religa D, et al. Strong association between Saitohin gene polymorphism and tau haplotype in the Polish population. Neurosci Lett 2003; 348: 163–166.
- 23 Zappia M, Annesi G, Nicoletti G, et al. Association of tau gene polymorphism with Parkinson's disease. Neurol Sci 2003; 24: 223–224.
- 24 Clark LN, Levy G, Tang MX, et al. The Saitohin ‘Q7R’ polymorphism and tau haplotype in multi-ethnic Alzheimer disease and Parkinson's disease cohorts. Neurosci Lett 2003; 347: 17–20.
- 25 Johansson A, Zetterberg H, Hakansson A, et al. TAU haplotype and the Saitohin Q7R gene polymorphism do not influence CSF Tau in Alzheimer's disease and are not associated with frontotemporal dementia or Parkinson's disease. Neurodegener Dis 2005; 2: 28–35.
- 26 Fidani L, Kalinderi K, Bostantjopoulou S, et al. Association of the Tau haplotype with Parkinson's disease in the Greek population. Mov Disord 2006; 21: 1036–1039.
- 27 Fung HC, Scholz S, Matarin M, et al. Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data. Lancet Neurol 2006; 5: 911–916.
- 28 Fung HC, Xiromerisiou G, Gibbs JR, et al. Association of tau haplotype-tagging polymorphisms with Parkinson's disease in diverse ethnic Parkinson's disease cohorts. Neurodegener Dis 2006; 3: 327–333.
- 29 Papapetropoulos S, Farrer MJ, Stone JT, et al. Phenotypic associations of tau and ApoE in Parkinson's disease. Neurosci Lett 2007; 414: 141–144.
- 30 Pittman AM, Myers AJ, Abou-Sleiman P, et al. Linkage disequilibrium fine-mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet 2005; 42: 837–846.
- 31 Rademakers R, Melquist S, Cruts M, et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 2005; 14: 3281–3292.
- 32 Mueller JC, Fuchs J, Hofer A, et al. Multiple regions of α-synuclein are associated with Parkinson's disease. Ann Neurol 2005; 57: 535–541.
- 33 Berg D, Niwar M, Maass S, et al. Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients. Mov Disord 2005; 20: 1191–1194.
- 34 Williams-Gray CH, Goris A, Foltynie T, et al. No alterations in alpha-synuclein gene dosage observed in sporadic Parkinson's disease. Mov Disord 2006; 21: 731–732.
- 35 Mizuta I, Satake W, Nakabayashi Y, et al. Multiple candidate gene analysis identifies alpha-synuclein as a susceptibility gene for sporadic Parkinson's disease. Hum Mol Genet 2006; 15: 1151–1158.
- 36 Maraganore DM, de Andrade M, Elbaz A, et al. Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA 2006; 296: 661–670.
- 37 Kwok JB, Teber ET, Loy C, et al. Tau haplotypes regulate transcription and are associated with Parkinson's disease. Ann Neurol 2004; 55: 329–334.
- 38 Caffrey TM, Joachim C, Paracchini S, et al. Haplotype-specific expression of exon 10 at the human MAPT locus. Hum Mol Genet 2006; 15: 3529–3537.
- 39 Myers AJ, Pittman AM, Zhao AS, et al. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis 2007; 25: 561–570.
- 40 Zhang Y, James M, Middleton FA, et al. Transcriptional analysis of multiple brain regions in Parkinson's disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 2005; 137: 5–16.
- 41 Moran LB, Duke DC, Deprez M, et al. Whole genome expression profiling of the medial and lateral substantia nigra in Parkinson's disease. Neurogenetics 2006; 7: 1–11.
- 42 Cordell HJ. Epistasis: what it means, what it doesn't mean, and statistical methods to detect it in humans. Hum Mol Genet 2002; 11: 2463–2468.
- 43 Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003; 300: 636–640.
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