PARK8 (LRRK2)

PARK8 was first described in a Japanese family exhibiting autosomal dominant parkinsonism (Funayama et al., 2002), but subsequently in Caucasian families, as well (Zimprich et al., 2004). Mutations within the gene for leucine-rich repeat kinase 2 (LRRK2) were later found to underlie the PARK8 association with PD (Paisán-Ruíz et al., 2004; Zimprich et al., 2004). One particular mutation, G2019S, has been identified in about 1% of sporadic cases and 4% of familial cases (Healy et al., 2008). The frequency of this mutation is even higher (13-40%) in certain populations such as North African Arab-Berbers and Ashkenazi Jews (Ozelius et al., 2006; Lesage et al., 2006). Penetrance of the LRRK2 G2019S mutation increases with age, with estimates between 35-85%. Several less frequent pathogenic mutations in LRRK2 have also been found, including R1441C, R1441G, R1441H, Y1699C and I2020T (Gasser, 2009).

In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations (Gasser, 2009).

Clinically, LRRK2-associated PD presents with typical L-DOPA-responsive parkinsonism and an age of onset generally in the late-fifties (although this can vary widely). Disease progression appears somewhat slower and less severe, with lower incidence of dementia (Healy et al., 2008). LRRK2-associated PD exhibits mostly a classic, Lewy body pathology, but occurrence of other protein inclusion forms, as well as nigral cell loss without clear presence of protein deposition, have been reported (Gasser, 2009).

LRRK2 contains multiple protein-binding and catalytic domains, including a Roc-GTPase domain and a kinase domain similar to both receptor-interacting and tyrosine kinases. Its function remains elusive, and mutations are found within many regions of the gene. Several mutations lead to an apparent gain-of-function in the kinase activity of LRRK2, which can result in cell death (Moore, 2008). This apparent enhanced pathological kinase activty has made LRRK2 an attractive target for future therapeutic intervention.