Modeling LRRK2 Parkinsonism

Abstract

Mutations in the LRRK2 gene were first described in 2004 and have now emerged as the most important genetic finding in Parkinson’s Disease (PD) (Paisan-Ruiz et al., 2004, Zimprich et al., 2004). Incredibly, they account for up to 40% of familial parkinsonism in certain ethnic populations (Ishihara et al., 2007; Kachergus et al., 2005; Ozelius et al., 2006). Moreover LRRK2 mutations also are responsible for about 2 % of PD in sporadic (idiopathic) patients and two risk factors increase the risk for sporadic PD in Asian populations by twofold (Di Fonzo et al., 2006; Farrer et al., 2007; Ross et al., 2008; Tan, 2006). While the precise functional role of LRRK2 protein is still emerging, it has attracted intense pharmaceutical interest as a highly “druggable” target. This, and other unique properties including variable penetrance and pathologies that overlap with other neurodegenerative disorders, have fueled theories that a LRRK2 therapeutic will benefit not just familial parkinsonism, but also sporadic parkinsonism and perhaps even neurodegeneration in general. Development of LRRK2 agents relies on the availability of animal models, which provide not only information of physiological and pathological functions but also a means for testing and phenotypic reversal. In this chapter we summarize the progress to date for both invertebrate and vertebrate models of LRRK2 parkinsonism and briefly discuss opportunities for therapeutic development.