Unraveling LRRK2 pathogenesis: common pathways for complex genes?

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see Review of Ng et al. Parkinson's disease (PD) is the second most common neurodegenerative disease affecting the Western world. The disease in humans is characterized by the selective loss of dopaminergic neurons in the sub-stantia nigra pars compacta; however, modeling this disease in transgenic animals has proven exceptionally difficult. Until recently, knockout murine models for the PD-associated genes LRRK2, ␣-synuclein, Parkin, PINK1, and DJ-1 have typically failed to generate a comparable pathological setting to aid basic and therapeutic research into PD pathogene-sis. Researchers have therefore used genetic manipulation in Drosophila to gain insight into the signaling pathways affected in PD. Typically, these fly models consist of either RNA-interference-or P-element-generated knockouts and/or overexpression of the mutated genes associated with PD. One of the more recent proteins to be assessed in Drosophila is LRRK2, mutations of which can induce dominantly inherited, late-onset PD. LRRK2 is a formidable protein, which can be difficult to express due to its large size (280 kDa) and is likely to influence a number of cellular functions due to its multidomain structure including a Roc (Ras of complex), COR (C terminal of Roc), serine/threonine kinase domain, and several WD40 repeat protein–protein interaction domains. Although the PD-associated mutations in LRRK2 are located throughout the protein, several studies have reported that an increase in kinase activity is associated with patho-genesis. Consequently, the identification of LRRK2 substrates and inhibitors has been a key focus of recent investigations (Nichols et al., 2009). The recent publication by Ng et al. (2009) in The Journal of Neuroscience assessed the effects of overexpressing LRRK2 wild-type (wt) and PD-associated mutations on age-dependent dopami-nergic (DA), tyrosine hydroxylase-positive (THϩ) neuron loss, altered dopamine levels, and climbing defects in flies. Unlike most previous studies, in which the Dro-sophila LRRK2 homolog (dLRRK) was overexpressed or knocked out, Ng et al. (2009) specifically expressed the human wt, G2019S, Y1699C, and G2385R LRRK2 variant proteins in the wt fly eye and brain. The location of these mutations within the kinase, COR, and WD40 domains , respectively, permit the authors to determine whether mutations within the different protein domains of LRRK2 can induce …