LRRK2 gene mutations are a common cause of Parkinsons disease. The protein product of the gene has both kinase and GTPase activities. Because there are mutations in both kinase and GTPase domains, we consider that both activities are probably important for pathogenesis of Parkinsons disease. As such, we are trying to understand each activity in turn and how they interact. We have worked to show that the effects of Lrrk2 deficiency in vivo result in accumulation of lysosomal enzymes. While we are still working on the precise mechanism by which this occurs, we know that lysosomal enzyme accumulation occurs earlier in the aging process than other changes that relate to protein translation and cytoskeletal derangements. Importantly, these changes are not seen with animals who have a pathogenic mutation in Lrrk2 knocked in to their genome. In the context of several other observations from our lab, these data show clearly that mutations in Lrrk2 do not cause disease by loss of function, supporting the idea that inhibition of this enzyme might be therapeutically useful for Parkinson's disease. We have also examined the relationship between LRRK2 and the Rab family of small GTPases that we have previously nominated as protein interaction partners of LRRK2 and have more recently been identified as substrates for the kinase activity of LRRK2. We have shown that RAB29 directs LRRK2 to the trans-Golgi network where LRRK2 is activated, measured by accumulation of autophosphorylation. These data define at least some of the pathway by which LRRK2 interacts with risk factor genes for PD.
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