Objective: The objective of this study is to characterise the biochemical and cellular impact of the G2385R coding variant in LRRK2, a risk variant for Parkinson’s in East Asian populations

Background: Autosomal dominant mutations in LRRK2 are the most common genetic cause of Parkinson’s, however the LRRK2 gene is noteworthy for additional coding and non-coding risk associated with the disease risk. This includes the G2385R variant, found in East Asian populations, associated with an odds ratio of 2.69. In contrast to autosomal dominant mutations described to date, which reside exclusively within the enzymatic core of LRRK2, the G2385R variant is located in the carboxy terminus WD40 scaffolding domain. The precise biochemical mechanisms underlying the association of this variant with heightened disease risk are unclear.

Method: To assess the impact of the G2385R variant, we have carried out an exhaustive analysis of signalling pathways and cellular events linked to LRRK2 following expression of the G2385R variant in HEK293 cells. This has been achieved using phosphospecific immunoblot read outs for LRRK2 kinase activity, coupled with live cell imaging and validated LRRK2 stimulators including L-Leucyl-L-Leucine methyl ester (LLOME).

Results: Our results support a distinct mechanism of action for G2385R, with a reduced impact on enzymatic activity compared to mutations in the ROC-COR-Kinase core of LRRK2, and altered cellular localisation compared to other variants.

Conclusion: The frequency of the G2385R variant, and distinct mechanism of action, highlight targeting the WD40 domain as an important unexploited opportunity for drug discovery modulating the activity of LRRK2. Further investigations into the structural basis for the association of G2385R with disease, coupled with

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-cellular-consequences-of-the-g2385r-lrrk2-variant/