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The Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders

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Abstract

Mutations in the gene encoding glucocerebrosidase (GBA), the enzyme deficient in the lysosomal storage disorder Gaucher disease, are associated with the development of Parkinson disease and other Lewy body disorders. In fact, GBA variants are currently the most common genetic risk factor associated with parkinsonism, and identified subjects with Parkinson disease are more than five times more likely to carry mutations in GBA. The mechanisms underlying this association are not known, but proposed theories include enhanced protein aggregation, alterations in lipid levels, and autophagy-lysosomal dysfunction promoting the retention of undegraded proteins. We review the genetic studies linking GBA to parkinsonism, as well as several of the mechanisms postulated to explain the association of GBA mutations and the synucleinopathies, which demonstrate how studies of a rare mendelian disease may provide insights into our understanding of a common complex disorder.

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Acknowledgments

This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health. The authors thank Dr. Nahid Tayebi, Dr. Grisel Lopez, Dr. Ehud Goldin, Sarah Klontz, and Jae H. Choi for their critical reading of the manuscript.

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  1. Section on Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Building 35, Room 1A213, 35 Convent Drive, MSC 3708, Bethesda, MD, 20892, USA

    Arash Velayati & Ellen Sidransky

  2. Taub Institute for Alzheimer’s Disease Research, Department of Pathology, Columbia University, New York, NY, USA

    W. Haung Yu

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  1. Arash Velayati
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Correspondence to Ellen Sidransky.

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Velayati, A., Yu, W.H. & Sidransky, E. The Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders. Curr Neurol Neurosci Rep 10, 190–198 (2010). https://doi.org/10.1007/s11910-010-0102-x

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