Guilt-by-Association - Functional Insights Gained From Studying the LRRK2 Interactome

The Parkinson's disease-associated Leucine-rich repeat kinase 2 (LRRK2) is a complex multi-domain protein belonging to the Roco protein family, a unique group of G-proteins. Variants of this gene are associated with an increased risk of Parkinson's disease. Besides its well-characterized enzymatic activities, conferred by its GTPase and kinase domains, and a central dimerization domain, it contains four predicted repeat domains, which are, based on their structure, commonly involved in protein-protein interactions (PPIs). In the past decades, tremendous progress has been made in determining comprehensive interactome maps for the human proteome. Knowledge of PPIs has been instrumental in assigning functions to proteins involved in human disease and helped to understand the connectivity between different disease pathways and also significantly contributed to the functional understanding of LRRK2. In addition to an increased kinase activity observed for proteins containing PD-associated variants, various studies helped to establish LRRK2 as a large scaffold protein in the interface between cytoskeletal dynamics and the vesicular transport. This review first discusses a number of specific LRRK2-associated PPIs for which a functional consequence can at least be speculated upon, and then considers the representation of LRRK2 protein interactions in public repositories, providing an outlook on open research questions and challenges in this field.