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Genetics of Mendelian Forms of Parkinson’s Disease

  • Chapter
Movement Disorder Genetics

Abstract

Over the past decade, genetic causes of parkinsonism have been elucidated but in less than 10 % of the cases. Since the discovery of the first gene responsible for Parkinson’s disease (PD), SCNA encoding α-synuclein, linkage mapping, and positional cloning have identified autosomal dominantly or recessively inherited PD-causing mutations in the genes encoding Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, leucine-rich repeat kinase 2 (LRRK2), and ATP13A2, indicating that PD has a highly heterogeneous etiology. With the introduction of next-generation sequencing, rare mutations in DNAJC6, SYNJ1, VPS35 , and DNAJC13 were then discovered to cause inherited parkinsonism. In addition, polymorphic variants in SNCA and LRRK2 and heterozygous mutations in the genes encoding β-glucocerebrosidase (GBA) and guanosine triphosphate cyclohydrolase 1 (GCH1) appear to contribute to sporadic PD in several populations. These mutations have been linked to mitochondrial dysfunction, accumulation of abnormal and misfolded proteins, impaired protein clearance, defective recycling of synaptic vesicles, and oxidative stress. Identification of other Mendelian forms of PD will be the main challenge for the next decade.

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Acknowledgments

The author is grateful to Dr. Merle Ruberg for critical reading of the manuscript. This work was supported by the National Research Funding Agency (ANR-08-NEUR-004-01) in association with ERA-NET NEURON, the France-Parkinson Association, and the French program “Investissements d’avenir” (ANR-10-IAIHU-06).

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  1. INSERM U M27, Pitié-Salpêtrière Hospital, Brain and Spinal Cord Institute (ICM), Paris, 75013, France

    Suzanne Lesage PhD

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Correspondence to Suzanne Lesage PhD .

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  1. Department of Neurology, University Hospital Kiel, Kiel, Germany

    Susanne A. Schneider

  2. Department of Molecular Neuroscience, University College London, Institute of Neurology, London, United Kingdom

    José M. Tomás Brás

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Lesage, S. (2015). Genetics of Mendelian Forms of Parkinson’s Disease. In: Schneider, S., Brás, J. (eds) Movement Disorder Genetics. Springer, Cham. https://doi.org/10.1007/978-3-319-17223-1_1

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  • DOI: https://doi.org/10.1007/978-3-319-17223-1_1

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