Analysis of Parkinson's disease brain–derived DNA for alpha-synuclein coding somatic mutations

Authors

  • Christos Proukakis PhD, FRCP,

    Corresponding author
    1. Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom
    • Correspondence to: Dr. Christos Proukakis, Institute of Neurology, University College London, Department of Clinical Neurosciences, Rowland Hill Street, London NW3 2PF, United Kingdom, E-mail: c.proukakis@ucl.ac.uk

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  • Maryiam Shoaee PhD,

    1. Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom
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  • James Morris,

    1. Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom
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  • Timothy Brier PhD, MBBS,

    1. Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom
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  • Eleanna Kara MSc, MBBS,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College, London, London
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  • Una-Marie Sheerin MRCP,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College, London, London
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  • Gavin Charlesworth MRCP,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College, London, London
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  • Eduardo Tolosa MD,

    1. Neurology Service, Hospital Clínic de Barcelona, Universitat de Barcelona, IDIBAPS, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain
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  • Henry Houlden PhD, FRCP,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College, London, London
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  • Nicholas W. Wood PhD, FRCP,

    1. Department of Molecular Neuroscience, Institute of Neurology, University College, London, London
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  • Anthony H. Schapira DSc, FRCP, MD, FMedSci

    1. Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom
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  • Funding agencies: This study was supported by grants from Parkinson's UK (Innovation Grant K-1111), and the Wellcome Trust / MRC joint call in Neurodegeneration strategic award (WT089698). DNA extraction work was partly undertaken at University College London Hospitals, University College London, who received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding. Tissue samples and associated clinical and neuropathological data were supplied amongst others by the Parkinson's UK Tissue Bank, funded by Parkinson's UK, a charity registered in England and Wales (258197) and in Scotland (SC037554).

  • 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

Background

Although alpha-synuclein (SNCA) is crucial to the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), mutations in the gene appear to be rare. We have recently hypothesized that somatic mutations in early development could contribute to PD.

Methods

Expanding on our recent negative small study, we used high-resolution melting (HRM) analysis to screen SNCA coding exons for somatic point mutations in DNA from 539 PD and DLB cerebellar samples, with two additional regions (frontal cortex, substantia nigra) for 20 PD cases. We used artificial mosaics to determine sensitivity where possible.

Results

We did not detect any evidence of somatic coding mutations. Three cases were heterozygous for known silent polymorphisms. The protocol we used was sensitive enough to detect 5% to 10% mutant DNA.

Conclusion

Using DNA predominantly from cerebellum, but also from frontal cortex and substantia nigra (n = 20 each), we have not detected any somatic coding SNCA point mutations. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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