Dictyostelium discoideum: A Model System to Study LRRK2-Mediated Parkinson Disease

Abstract

Parkinson disease (PD) is a neurodegenerative disease that affects more than 5 million people worldwide and one in hundred people over the age of 60. PD is both a chronic and degenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra, associated with the formation of fibrillar aggregates composed of synuclein and other proteins (Lees et al., 2009). PD is clinically characterized by tremor, bradykinesia, rigidity and postural instability. Initially PD was considered to have no genetic cause, however many patients have one or more family member with the disease and genome-wide association studies identified a number of genetic factors segregating with PD (Satake et al., 2009; Simon-Sanchez et al., 2009). Therefore, it is now general believed that PD is caused by a combination of genetic and environmental factors. Recently, missense mutations in LRRK2 have been linked to autosomal-dominant, late-onset PD (Zimprich et al., 2004;Paisan-Ruiz et al., 2004). LRRK2 is a member of the novel Roco family of complex Ras-like GTPases that have an unique domain architecture (Fig. 1) (Bosgraaf and van Haastert, 2003). Roco proteins are characterized by the presence of a Ras-like Guanine nucleotide binding domain, called Roc (Ras of complex proteins), followed by a conserved stretch of 300-400 amino-acids with no significant homology to other described protein domains called the COR domain (C-terminal of Roc; Fig. 1). The Roc and COR domains always occurs as a pair, and so far no proteins have been identified containing either the Roc or COR domain alone, suggesting that these two domains function as one inseparable unit. Roco proteins were first identified in the social amoeba Dictyostelium discoideum and are found in prokaryotes, plants and metazoa, but not in Plasmodium and yeast (Bosgraaf et al., 2003). Besides a Roc and COR domain, all Roco proteins contain an N-terminal stretch of leucine-rich repeats (LRR), which are supposed to be involved in protein-protein interaction. A large group of Roco proteins, which is only present in Dictyostelium and metazoan, contains an additional C-terminal kinase domain of the MAPKKK subfamily of kinases. Next to this general domain composition, individual Roco proteins are found to be combined with a diversity of additional domains such as Guanine nucleotide exchange factor (GEF) and Regulator of G-protein Signalling (RGS) domains, implicating a link between traditional G-protein signalling pathways and Roco proteins (Bosgraaf et al., 2003). The identification of missense mutations in LRRK2 has redefined the role of genetic variation in PD susceptibility. LRRK2 mutations initiate a penetrant phenotype with