Leucine-rich repeat kinase 2 (LRRK2): a key player in the pathogenesis of Parkinson's disease

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, with a prevalence of more than 1% after the age of 65 years. Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have recently been linked to autosomal dominant, late-onset PD that is clinically indistinguishable from typical, idiopathic disease. LRRK2 is a multidomain protein containing several protein interaction motifs as well as dual enzymatic domains of GTPase and protein kinase activities. Disease-associated mutations are found throughout the multidomain structure of the protein. LRRK2, however, is unique among the PD-causing genes, because a missense mutation, G2019S, is a frequent determinant of not only familial but also sporadic PD. Thus, LRRK2 has emerged as a promising therapeutic target for combating PD. In this Mini-Review, we look at the current state of knowledge regarding the domain structure, amino acid substitutions, and potential functional roles of LRRK2.

Fig. 1. Schematic representation of the predicted LRRK2 domain structure

LRRK2 is composed of 13 LRRs, followed by the Roc, COR, and MAPKKK domains, as well as seven WD40 repeats at the C-terminus. Mutations that are considered definitively pathogenic are shown in red. Amino acid substitutions that can act as risk factors for disease and are putatively pathogenic are shown in green. Mutations that have been identified in PD patients but for which pathogenicity is uncertain are shown in blue. The amino acid residue numbers beneath each domain indicates the estimated domain boundaries. Predicted functions of each of the LRRK2 domains are listed. The GenBank accession number for human LRRK2 is AAV63975.