Abstract
Mutations in LRRK2 are a common cause of familial and idiopathic Parkinson’s disease (PD). Recently, the LRRK2 GTPase domain R1398H variant was suggested in genetic studies to confer protection against PD but mechanistic data supporting this is lacking. Here, we present evidence that R1398H affects GTPase function, axon outgrowth, and Wnt signaling in a manner opposite to pathogenic LRRK2 mutations. LRRK2 R1398H GTPase domain dimerization and GTP hydrolysis were increased whereas GTP binding was reduced, leading to a decrease in active GTP-bound LRRK2. This protective variant also increased axon length of primary cortical neurones in comparison to wild-type LRRK2, whereas the R1441G LRRK2 pathogenic mutant decreased axon outgrowth. Importantly, R1398H enhanced the stimulatory effect of LRRK2 on canonical Wnt signaling whereas the G2385R risk variant, in accordance with all previously tested pathogenic LRRK2 mutants, had the opposite effect. Molecular modeling placed R1398H in close proximity to PD-causing mutations suggesting that this protective LRRK2 variant, like familial mutations, affects intramolecular RocCOR domain interactions. Thus, our data suggest that R1398H LRRK2 is a bona fide protective variant. The opposite effects of protective versus PD associated LRRK2 variants on GTPase function and canonical Wnt signaling activity also suggests that regulation of these two basic signaling mechanisms is important for neuronal function. We conclude that LRRK2 mediated Wnt signaling and GTPase function are fundamental in conferring disease susceptibility and have clear implications for therapeutic target identification.
Highlights
Autosomal-dominant mutations in LRRK2, encoding leucine-rich repeat kinase 2 (LRRK2), are the most common known cause of inherited Parkinson’s disease (PD; Paisán-Ruíz et al, 2004; Zimprich et al, 2004)
To investigate functional effects of R1398H, we studied this variant in assays of LRRK2 RocCOR domain dimerization
These sensitive quantitative yeast-two hybrid (Q-YTH) assays have been used previously in our laboratory to show that the PD-causing R1441C, R1441G, R1441H, and Y1699C mutations significantly weaken RocCOR domain dimerization (Daniëls et al, 2011)
Summary
Autosomal-dominant mutations in LRRK2, encoding leucine-rich repeat kinase 2 (LRRK2), are the most common known cause of inherited Parkinson’s disease (PD; Paisán-Ruíz et al, 2004; Zimprich et al, 2004). LRRK2 is a multifunctional protein containing both kinase and GTPase activities and a number of protein–protein interaction domains (Figure 1). The ‘catalytic core’ is contained within the Roc (Ras of complex proteins), COR (C-terminal of Roc) and kinase domains (Figure 1) and appears essential for LRRK2 function (Berwick and Harvey, 2011). As the only hereditary mutations that are proven to cause PD fall within exons coding for the Roc, COR and kinase domains, the effects of pathogenic mutations on LRRK2 enzymatic activities require further investigation
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