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Lee CY, Menozzi E, Chau KY, et al. Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes. J Neurochem. 2021;159(5):826-839doi: 10.1111/jnc.15524.
Lee, C. Y., Menozzi, E., Chau, K. Y., & Schapira, A. H. V. (2021). Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes. Journal of neurochemistry, 159(5), 826-839. https://doi.org/10.1111/jnc.15524
Lee, Chiao-Yin, et al. "Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes." Journal of neurochemistry vol. 159,5 (2021): 826-839. doi: https://doi.org/10.1111/jnc.15524
Lee CY, Menozzi E, Chau KY, Schapira AHV. Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes. J Neurochem. 2021 Dec;159(5):826-839. doi: 10.1111/jnc.15524. Epub 2021 Oct 16. PMID: 34618942.
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J Neurochem. 2021 Dec;159(5):826-839. doi: 10.1111/jnc.15524. Epub 2021 Oct 16.

Glucocerebrosidase 1 and leucine-rich repeat kinase 2 in Parkinson disease and interplay between the two genes.

Journal of neurochemistry

Chiao-Yin Lee, Elisa Menozzi, Kai-Yin Chau, Anthony H V Schapira

Affiliations

  1. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
  2. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA.

PMID: 34618942 DOI: 10.1111/jnc.15524

Abstract

The glucocerebrosidase 1 gene (GBA1), bi-allelic variants of which cause Gaucher disease (GD), encodes the lysosomal enzyme glucocerebrosidase (GCase) and is a risk factor for Parkinson Disease (PD). GBA1 variants are linked to a reduction in GCase activity in the brain. Variants in Leucine-Rich Repeat Kinase 2 (LRRK2), such as the gain-of-kinase-function variant G2019S, cause the most common familial form of PD. In patients without GBA1 and LRRK2 mutations, GCase and LRRK2 activity are also altered, suggesting that these two genes are implicated in all forms of PD and that they may play a broader role in PD pathogenesis. In this review, we review the proposed roles of GBA1 and LRRK2 in PD, focussing on the endolysosomal pathway. In particular, we highlight the discovery of Ras-related in brain (Rab) guanosine triphosphatases (GTPases) as LRRK2 kinase substrates and explore the links between increased LRRK2 activity and Rab protein function, lysosomal dysfunction, alpha-synuclein accumulation and GCase activity. We also discuss the discovery of RAB10 as a potential mediator of LRRK2 and GBA1 interaction in PD. Finally, we discuss the therapeutic implications of these findings, including current approaches and future perspectives related to novel drugs targeting LRRK2 and GBA1.

© 2021 International Society for Neurochemistry.

Keywords: GBA1; Gaucher disease; LRRK2; Parkinson disease; glucocerebrosidase; neurodegeneration

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