Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions

Abstract

Mutations in the gene encoding LRRK2 (leucine-rich repeat kinase 2) were first identified in 2004 and have since been shown to be the single most common cause of inherited Parkinson's disease. The protein is a large GTP-regulated serine/threonine kinase that additionally contains several protein-protein interaction domains. In the present review, we discuss three important, but unresolved, questions concerning LRRK2. We first ask: what is the normal function of LRRK2? Related to this, we discuss the evidence of LRRK2 activity as a GTPase and as a kinase and the available data on protein-protein interactions. Next we raise the question of how mutations affect LRRK2 function, focusing on some slightly controversial results related to the kinase activity of the protein in a variety of in vitro systems. Finally, we discuss what the possible mechanisms are for LRRK2-mediated neurotoxicity, in the context of known activities of the protein.

Figure 1. LRRK2 mutations and domains

Many variants in LRRK2 have been reported; some are clearly pathogenic, some are clearly not pathogenic and many are unclear. The tests for pathogenicity are either segregation (blue box) within families or association with disease across populations (yellow box) and mutations that pass either of these tests are placed in an approximate relationship to the linear sequence of the protein. Some mutations, such as R1441H, are probably causal but segregation data is less clear and these are listed in the grey box. Finally, a large number of polymorphic variants have been reported that are not likely to be pathogenic (white box). For the sake of clarity, not all reported mutations are listed. Here, we show only non-synonymous amino-acid-changing variants that were found only in controls (Paisán-Ruíz et al., 2008) and thus are very unlikely to be related to disease. The ideogram in the lower part of the Figure shows LRRK2 in a linear arrangement with each of the proposed domains labelled, from N- to C-termini; ANK, ankyrin-like repeats; LRR, leucine-rich repeats; ROC, Ras of complex proteins, GTPase domain; COR, C-terminal of ROC domain; kinase; WD40, a β-propeller-like domain made up of WD40 repeats. It should be noted that the clearly pathogenic variants cluster around the central enzymatic region, whereas clearly polymorphic changes are distributed throughout the molecule.

Figure 2. Effects of LRRK2 mutations on kinase activity

For this Figure, we took reported effects of LRRK2 mutations on kinase activity and expressed each relative to the wild-type LRRK2 reported in the same study, where the broken line across the graph = 1. Each study is given by first author and year and the different symbols are colour-coded by substrate used in the assay; black, MBP; red, autophosphorylation; blue, LRRKtide peptide; purple, 4E-BP. Of all the mutations tested, the one that consistently shows an increased activity is G2019S in the kinase domain; all of the others vary between experiments, and there is no clear pattern that relates to substrate used.