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Gaucher disease provides a unique window into Parkinson disease pathogenesis

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From Nature Reviews Neurology

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Abstract

An exciting development in the field of neurodegeneration is the association between the rare monogenic disorder Gaucher disease and the common complex disorder Parkinson disease (PD). Gaucher disease is a lysosomal storage disorder resulting from an inherited deficiency of the enzyme glucocerebrosidase, encoded by GBA1, which hydrolyses the glycosphingolipids glucosylceramide and glucosylsphingosine. The observation of parkinsonism in a rare subgroup of individuals with Gaucher disease first directed attention to the role of glucocerebrosidase deficiency in the pathogenesis of PD. PD occurs more frequently in people heterozygous for Gaucher GBA1 mutations, and 3–25% of people with Parkinson disease carry a GBA1 variant. However, only a small percentage of individuals with GBA1 variants develop parkinsonism, suggesting that the penetrance is low. Despite over a decade of intense research in this field, including clinical and radiological evaluations, genetic studies and investigations using model systems, the mechanism underlying GBA1-PD is still being pursued. Insights from this association have emphasized the role of lysosomal pathways in parkinsonism. Furthermore, different therapeutic strategies considered or developed for Gaucher disease can now inform drug development for PD.

Key points

  • The rare, autosomal recessively inherited disorder Gaucher disease is providing new insights into the pathogenesis of Parkinson disease.

  • Variants in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are the most common known genetic risk factor for Parkinson disease and dementia with Lewy bodies.

  • Most individuals with homozygous or heterozygous GBA1 variants do not develop parkinsonism. Identifying the factors that impact penetrance will be crucial to our understanding of disease mechanisms.

  • Therapeutic strategies under development for Gaucher disease, such as brain-penetrant enzyme replacement strategies, gene therapy approaches, and small molecule chaperones and activators, might inform new treatment approaches for Parkinson disease.

  • Improved clinical biomarkers are needed to identify GBA1 variant carriers early in their disease course to enable preventative therapies.

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Fig. 1: The spectrum of manifestations encountered in Parkinson disease and in Gaucher disease.
Fig. 2: Pathogenicity of Gaucher disease and Parkinson disease.
Fig. 3: Therapeutic strategies for Gaucher disease and Parkinson disease.

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Acknowledgements

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 J. Fekecs for her assistance with drafting the figures.

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  1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Ellen Hertz, Yu Chen & Ellen Sidransky

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Hertz, E., Chen, Y. & Sidransky, E. Gaucher disease provides a unique window into Parkinson disease pathogenesis. Nat Rev Neurol 20, 526–540 (2024). https://doi.org/10.1038/s41582-024-00999-z

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