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Advances in the genetics of Parkinson disease

Nature Reviews Neurology volume 9, pages 445–454 (2013)Cite this article

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Abstract

Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies.

Key Points

  • Parkinson disease (PD) is a multifactorial disorder that, in most cases, results from genetic and environmental factors

  • Approaches to study the genetics of PD include linkage analysis, genome sequencing and association studies

  • Many genes, mutations and polymorphisms have implicated in PD pathogenesis

  • Genetic discoveries highlight biological processes and pathways that are consistently perturbed in idiopathic PD, although individual results are seldom useful for a patient diagnosis

  • Identification of such genetic variability may inform the design of clinical trials and future therapeutic strategies

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Figure 1: Key molecular processes implicated in parkinsonism by genetic findings and extrapolated in models of disease.

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Acknowledgements

The work of the authors is funded by the Leading Edge Endowment Fund (to J. Trinh), and through a Canada Excellence Research Chair and the Don Rix Chair in Genetic Medicine (to M. Farrer).

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  1. Department of Medical Genetics, UBC Pavillion Hospital, 2nd floor, Room S-132 Koerner Building, VCHRI, 2211 Wesbrook Mall, University of British Columbia, Vancouver, V6T 2B5, British Columbia, Canada

    Joanne Trinh & Matt Farrer

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Both authors researched data for the article and made substantial contributions to discussion of the content, writing of the article and to review and/or editing of the manuscript before submission.

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Trinh, J., Farrer, M. Advances in the genetics of Parkinson disease. Nat Rev Neurol 9, 445–454 (2013). https://doi.org/10.1038/nrneurol.2013.132

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