LRRK2

Four year ago, Parkinson's disease patients from families of Basque origin were found to carry a mutation which lead to the identification of the LRRK2 gene (previously known as Park8). The leucine-rich receptor kinase, dardarin, is a 286 kD modular protein containing seven modules, each of them with different function. Mutation occurred in a kinase, Roc, and Cor modules. So, it seems that some function related to these modules is altered in Parkinson's disease. But which one?

Newly generated transgenic mice give the clue. The mutation R1441G in the Ras in complex (Roc) GTPase domain produces Parkinsonian symptoms in the mice (Li et al., 2009). The mice develops bradikinesia by 10-12 months. The striatum also decreases the ability to release dopamine. To convince us of the results, Li and co-workers overexpressed the normal (WT) LRRK2 in other transgenic to find that they are normal. So the overexpression of protein is not what causes the parkinsonian symptoms in the mouse. The R1441G mutation doe not seems to cause too much damage. The authors find that dopaminergic neurones have sightly smaller soma and fragmented axons. Perhaps in the rush of publishing, they did not have time to study the function in more detail. They did study hyperphosphorylation of the tau protein. But tau is not the main feature of Parkinson disease.

So we still ignore how LRRK2 leads to Parkinson's disease. However, there have been some reports on how mutations at that position change the enzymatic activity. 

R1441C has been reported to decreases the GTPase activity (Lewis et al., 2007; Li et al., 2007) and to increase the kinase activity (West et al., 2005, Guo et al., 2007). Similar things happen for the mutant R1441G, it causes a decrease in the GTPase activity (Li et al., 2007). However, there has been a report in which none of the two mutations altered the kinase activity (Jaleel et al., 2007). An interesting insight comes from another study (Ho et al., 2008) in which LRRK2 is reported to interact with FADD, the death adaptor Fas-associated protein, related to caspase-8. Gloeckner and co-workers (2009) reported that LRRK2 can phosphorylate other kinases that mediate neurotoxicity and apoptosis. So the answer seems to be apoptosis after all.