**4.4 LRRK2 (PARK8) and paraquat**

In 2002, *PARK8* gene mutations were discovered as a major genetic cause associated with hereditary parkinsonism (Paisan-Ruiz *et al.*, 2004). The *PARK8* gene was associated with PD in studies of a Japanese Sagamihara family who responded positively to treatment with L-DOPA, which had parkinsonism that presented with an unknown aetiology of the disease (Funayama *et al.*, 2002). Other studies examined two additional families (German and Canadian) who also had an autosomal dominant, late-onset parkinsonism (Zimprich *et al.*, 2004).

In the LRRK2 structure, two functional domains, kinase and GTPase domains, were shown to be present. The G2019S mutation was present in the kinase domain specific to the binding site for Mg2+ (Kachergus *et al.*, 2005). This mutation facilitates the access of the kinase domain to its substrates, which increases autophosphorylation 2.5-fold the phosphorylation of other substrates, such as myelin basic protein (MBP), 3-fold for the LRRK2 autophosphorylation without the presence of this mutation (Jaleel *et al.*, 2007; West *et al.*, 2005), which is responsible for the increased toxicity of this molecule (Greggio *et al.*, 2006). In the GTPase domain, the R1441C has been the most studied mutation, and there is controversy as to the influence of GTPase mutations on the kinase activity that was observed in some studies in which the increase was similar (Guo *et al.*, 2007) or had no change (Jaleel *et al.*, 2007).

LRRK2 has been shown to play different roles in the cell; however, little information is available. Based on the data we found from the protein interactions, there was a relationship between LRRK2 and cytoskeletal reorganisation (Gandhi *et al.*, 2008), maintenance functions and cell morphology (Plowey *et al.*, 2008), protein transport through synaptic vesicles (Shin *et al.*, 2008), and the ubiquitination process (Ko *et al.*, 2009). There have also been studies that relate LRRK2 and apoptosis (Ho *et al.*, 2009). Previous studies have shown a relationship between LRRK2 and other PD-related proteins, such as parkin (Ng *et al.*, 2009; W. W. Smith *et al.*, 2005), PINK-1 and DJ-1 (Venderova *et al.*, 2009) or α-synuclein (X. Lin *et al.*, 2009). The interaction of LRRK2 with PQ is not clear. Studies in *Drosophila melanogaster* in which the deletion of kinase domain of LRRK2 did not induce a higher sensitivity to the PQ stimulus has been shown (D. Wang *et al.*, 2008). In contrast, in *Caenorhabditis elegans* studies, the expression of human LRRK2 protein protected against PQ, which increased nematode survival in response to agents that cause mitochondrial dysfunction. However, protection by G2019S, R1441C, or kinase-dead LRRK2 was less effective than wild-type LRRK2 (Saha *et al.*, 2009). In another study with *Caenorhabditits elegans, PINK1* mutant genes have been observed in a minor mitochondrial length and increased PQ sensitivity of the nematode. Moreover, the mutants also displayed defects in axonal outgrowth of a pair of canalassociated neurons. We demonstrated that in the absence of lrk-1 (the *C. elegans* homologue of human LRRK2), all phenotypic aspects of *PINK1* loss-of-function mutants were suppressed (Samann *et al.*, 2009)
