Three questions for LRRK2

As an outcome from our December 2009 LRRK2 Summit and various follow-up discussions, there are clearly a number of basic questions around LRRK2 function that remain unanswered (or only partially answered). Some of these relate to big meaty questions about physiological and pathological role of LRRK2 where we know a lot of work is now focused. However, other questions strike me more as methodological questions and I’m curious whether there are a few straight-forward studies that could be done to help clarify the field.

A good example of this relates to interpreting the large number of studies looking at role of pathogenic mutations in LRRK2 on kinase activity using the various available assays out there (e.g., LRRKtide, MBP, autophosphorylation). Although there appears to be good consensus that G2019S enhances activity in all of these assays, the impact of the other major mutations (e.g., R1441C/G, Y1699C, I2020T) is still seemingly uncertain. The effects of mutations on GTPase activity seem somewhat clearer (mutations reduce activity) but I may be oversimplifying that understanding.

Drs. Greggio and Cookson in their review last year suggested that one issue here may simply be the variety of different methods people are using that make outcomes hard to compare. Related to this, in various MJFF meetings discussing LRRK2 methods, questions around the impact of how you tag LRRK2 (i.e., C- or N-terminal) have also caused a lot of uncertainty in data interpretation.

With all of that being said, we’re very interested in developing a study or two that could tackle some of these questions in highly standardized and rigorous methodological fashion. I should say at the start that we’re not looking to simply fund an academic lab to do this; we were actually thinking of paying a company to do this via a contract mechanism. We would then make all the data available as quickly as possible either through a publication or better yet simply posting the data here on PD Online Research. Out goal is to focus on the kinds of studies that no one lab really has time or desire to tackle but feel would be critical data to have available.

So, my question to the community: What study(ies) should we design? What would help everyone get better clarity on some of these basic methodological questions for studying LRRK2? For those wishing to contribute ideas, please post your thoughts in response to my post.