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DNA methylation of the MAPT gene in Parkinson's disease cohorts and modulation by vitamin E In Vitro

Authors

  • Kirsten G. Coupland BSc,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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  • George D. Mellick PhD,

    1. Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia
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  • Peter A. Silburn PhD, FRACP,

    1. University of Queensland Centre for Clinical Research, Herston, Queensland, Australia
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  • Karen Mather PhD,

    1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
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  • Nicola J. Armstrong PhD,

    1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
    2. School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales, Australia
    3. School of Mathematics and Statistics and Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
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  • Perminder S. Sachdev MD,

    1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
    2. Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, New South Wales, Australia
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  • Henry Brodaty DSc,

    1. Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia
    2. Aged Care Psychiatry, Prince of Wales Hospital, Sydney, New South Wales, Australia
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  • Yue Huang MD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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  • Glenda M. Halliday PhD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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  • Marianne Hallupp BSc,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
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  • Woojin S. Kim PhD,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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  • Carol Dobson-Stone DPhil,

    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
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    • The last two authors are joint senior authors.

  • John B.J. Kwok PhD

    Corresponding author
    1. Neuroscience Research Australia, Sydney, New South Wales, Australia
    2. School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
    • Correspondence to: Dr. John Kwok, Neuroscience Research Australia, Barker Street, Randwick, Sydney, NSW, 2031 Australia; j.kwok@neura.edu.au

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    • The last two authors are joint senior authors.

Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 31, Issue 5, 768, Article first published online: 31 March 2016

  • Funding agencies: This study was supported by the National Health and Medical Research Council of Australia (NHMRC) seeding fund APP1021269, Program Grant 350833, and Capacity Building Grant 568940. G.M.H. was supported by an NHMRC Senior Principal Research Fellowship (630434).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methylation levels were determined by pyrosequencing of bisulfite-treated DNA in a leukocyte cohort (358 PD patients and 1084 controls) and in two brain cohorts (Brain1, comprising 69 cerebellum controls; and Brain2, comprising 3 brain regions from 28 PD patients and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. In normal leukocytes, the MAPT H1/H2 diplotype and sex were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed that the H1 haplotype had higher methylation than the H2 haplotype in normal leukocytes and brain tissues. MAPT methylation was negatively associated with MAPT expression in the Brain1 cohort and in transfected cells. Methylation levels differed between three normal brain regions (Brain2 cohort, putamen < cerebellum < anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood vitamin E levels, and the effect was more significant in H2 haplotype carriers; this result was confirmed in cells that were exposed to 100 μM vitamin E. The significant effects of sex, diplotype, and brain region suggest that hypermethylation of the MAPT gene is neuroprotective by reducing MAPT expression. The effect of vitamin E on MAPT represents a possible gene-environment interaction. © 2013 International Parkinson and Movement Disorder Society

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