The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease

Abstract

Parkinson's disease, like many common age-related conditions, is now recognized to have a substantial genetic component. Here, I discuss how mutations in a large complex gene--leucine-rich repeat kinase 2 (LRRK2)--affect protein function, and I review recent evidence that LRRK2 mutations affect pathways that involve other proteins that have been implicated in Parkinson's disease, specifically α-synuclein and tau. These concepts can be used to understand disease processes and to develop therapeutic opportunities for the treatment of Parkinson's disease.

Figure 1. Domains and mutations of LRRK2

LRRK2 is drawn schematically here as a dimer, in a likely head-to-head orientation and in a linear scheme for clarity. The domains of the protein and some of the proposed intramolecular interactions are listed above the diagram. LRRK2 is a large multidomain protein, with several potential protein–protein interaction regions surrounding a central catalytic core. This core region contains a GTP-binding Ras Of Complex protein domain (ROC), a C-terminal of ROC (COR) domain and a kinase domain. The most clearly defined pathogenic human mutations are shown in red below the diagram. Both R1441 and Y1699 mutations decrease the modest GTPase activity of LRRK2, while G2019S increases kinase activity. These two activities may be related as, for example, recent studies have indicated that the kinase domain (blue) autophosphorylates the ROC domain at several sites, although this has yet to be confirmed in vivo. Using current methods of measurement, I2020T seems to have very modest effects on kinase activity, so the relationship of that mutation to biochemical activities is unclear. Outside of the catalytic regions are several domains including the Leucine-rich repeats (LRR) and WD40 domains that are thought to provide protein-protein interaction regions, although specific binding partners for these regions are only recently starting to be identified (see text).

Figure 2. LRRK2, α-synuclein and tau

Human genetic, animal model and biochemical data support the idea that there are relationships between three gene products important in the genetic risk of familial and sporadic Parkinson’s disease, LRRK2, α-synuclein and tau. Here, I have put LRRK2 at the ‘top’ of the pathway, based on the observation that human cases with mutations in LRRK2 can have either α-synuclein or tau positive pathology and also that LRRK2 can accelerate (+ sign) α-synuclein pathology in a mouse model. Whether the same is true for LRRK2 and tau is not known, but I have made the assumption here that it could be. Finally, whether there is a truly triangular relationship in that Tau dysfunction can influence α-synuclein pathology or vice versa is unknown, and so this is indicated by a dotted line. Finally, the likely outputs of α-synuclein and tau dysfunction, namely changes in synaptic vesicle function and microtubule stability are indicated at the bottom of the diagram