Update on the functional biology of Lrrk2

Abstract

The etiology of Parkinson's disease (PD) was long thought to be due to environmental factors. Following the discovery of autosomal-dominant mutations in the α-synuclein gene, and later recessive mutations in the DJ-1, Parkin and PINK-1 genes, the field of PD genetics exploded. In 2004, it was discovered that mutations in the PARK8 locus - leucine-rich repeat kinase 2 (LRRK2, Lrrk2) - are the most important genetic cause of autosomal-dominant PD. Lrrk2 substitutions also account for sporadic PD in certain ethnic populations and have been shown to increase the risk of PD in Asian populations. Drug therapies targeting Lrrk2 activity may therefore be beneficial to both familial and sporadic PD patients, hence understanding the role of Lrrk2 in health and disease is critical. This review aims to highlight the research effort concentrated on elucidating the functional biological role of Lrrk2, and to provide some future therapeutic perspectives.

Figure 1. Lrrk2 protein showing predicted domains

Pathogenic substitutions are shown in black and substitutions associated with increase risk shown in white.

Figure 2. MAPKKK domain acids 1800–2138

The kinase active site (green) is centrally located alongside the ATP-binding region (turquoise). The activation segment (magenta) lies between conserved residues DYG and APE. Lrrk2 G2019S and I2020T mutations (indicated by arrow) change highly conserved glycine (G) and isoleucine (I) at the beginning of the activation segment. The activation segment typically blocks substrate access to the catalytic site. (Figure courtesy of J Johnson, Mayo Clinic).

Figure 3. Robust physiological expression of Lrrk2 in a mouse model

Immunoblot to show regional expression of Lrrk2 protein in human BAC transgenic mice using antibody PA0362 (Novus NB110-58771). Expression levels are approximately 20-fold over endogenous mouse Lrrk2.

Figure 4. Lrrk2 is expressed in regions of adult neurogenesis

Lrrk2 is expressed in chains of migrating neuroblasts in the subventricular zone. Red is polysialic acid–neural cell adhesion molecule (PSA-NCAM) a marker for migrating neuronal precursors, green is Lrrk2. Adapted from [94].