Glucocerebrosidase 1 and leucine‐rich repeat kinase 2 in Parkinson disease and interplay between the two genes. Issue 5 (16th October 2021)

• Record Type: Journal Article
• Authors: Lee, Chiao‐Yin; Menozzi, Elisa; Chau, Kai‐Yin; Schapira, Anthony H. V.
• Is Part Of: Journal of neurochemistry. Volume 159:Issue 5(2021)
• Page Start: 826
• Page End: 839
• Publication Date: 2021-10-16
• Subjects: Gaucher disease -- GBA1 -- glucocerebrosidase -- LRRK2 -- neurodegeneration -- Parkinson disease; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15524
• Languages: English
• ISSNs: 0022-3042

Abstract

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 . Abstract : Loss‐of‐function mutations in the glucocerebrosidase 1 ( GBA1 ) gene, coding for the lysosomal enzyme GCase, and gain‐of‐function mutations in the Leucine‐Rich Repeat Kinase 2 ( LRRK2) gene are risk factors for Parkinson disease (PD). In this review, we evaluate the proposed roles of GBA1 and LRRK2 in PD, focussing on the endolysosomal pathway and the possible interplay between the two genes. In particular, we explore the links between increased LRRK2 activity, Ras‐related‐in‐brain protein function, lysosomal dysfunction, alpha‐synuclein accumulation and GCase activity, and also discuss the therapeutic and diagnostic implications of these findings in the context of PD.