From Athens to Chicago: On our way to SFN2015!
Who we are? The details…We’re based at the Biomedical Research Foundation of the Academy of Athens, in Athens Greece; part of the Neurodegenerative Diseases Group headed by Prof. Leonidas Stefanis. Our team, led by Dr. Hardy Rideout, studies Parkinson’s disease that is caused by mutations in a gene called leucine-rich repeat kinase 2: LRRK2 for short! We are…Manuela (Masters student), Anna (PhD student), and Katerina (post-doctoral fellow).
What we are doing? The gene that we study, LRRK2, was discovered in 2004 to be linked to certain inherited forms of Parkinson’s disease. It is a very large gene (almost 150,000 bases in total!), and an error in just 1 or 2 of these bases is enough to alter the protein, and in some people lead to the development of Parkinson’s disease. The protein made by this gene (remember from high school, the information stored in our genes is used to make proteins!) is a special kind of protein known as a kinase; and it’s job is to regulate the activity of other proteins through a process called phosphorylation. To do this, LRRK2 takes one of the phosphates (P, in the picture) from ATP and attaches it to whatever protein it is trying to regulate. Some of the mutations in LRRK2 that lead to Parkinson’s disease cause this to happen more often, but we don’t understand why yet, or how this causes the disease.
When certain mutant forms of this protein are expressed in nerve cells that we grow in a dish, they form these striking filament-like structures (pictured here, in green). These are made up of pairs, or even more, of LRRK2 proteins. The main question we wanted to answer was whether or not the activity of this protein is more when it is alone, or in groups.
But…we needed to find a way to measure the activity of 2 different forms of LRRK2 from within the same cell! Ultimately we tricked the protein into doing the hard part of the work for us! And this is the really cool part: we engineered 2 different forms of LRRK2; and when they stick to each other, one will place a small “tag” on the other one. The LRRK2 proteins that prefer to hang out alone won’t have any “tag”. We can capture proteins labeled with this “tag” and then measure how active both types of the LRRK2 protein are. What we have been able to show so far is that when LRRK2 is alone, it seems to be more active than when it is in pairs or big groups of proteins.
So what, who cares? The fortunate part about LRRK2 is that, as a kinase, it is relatively easy to block its function with different drugs. So, once we confirm that the kinase function of LRRK2 is absolutely required for the development of Parkinson’s disease in some people, then one strategy is to use drugs that block this activity in patients suffering from the disease. In fact, now there is a huge effort in academic as well as commercial labs to develop very potent drugs that only block LRRK2, and have few side effects. Before we get to this point though, we need to fully understand how this kinase works, what kinds of things it regulates, and how it all goes wrong in Parkinson’s disease. What our work shows is that very specific forms of LRRK2 have widely different levels of activity, and only certain forms are thought to be responsible for causing the loss of nerve cells that leads to Parkinson’s disease. The hope is that we (as a larger community) can then design even more selective drugs that just target the “bad” activity of LRRK2, leaving the rest of its functions intact.
What do we need? Apart from being a beautiful place to live, and really an inspiring place to work, Greece is not exactly next door to Chicago! And, although we do have a few sources of funding from different Parkinson’s disease foundations (including the Michael J. Fox Foundation; https://www.michaeljfox.org/foundation/grant-detail.php?grant_id=1218), the money we receive must be used for primary research only, and not things like attending scientific conferences like the one we hope to go to in October. We turned to the crowdfunding platform for a number of reasons. First, it gives a chance for our donors to have a personal connection to the project they are helping support, in the form of experiencing the excitement of the SFN conference through Manuela’s daily blog and video journals. And secondly, RocketHub’s vision of supporting Science-based campaigns as well as allowing projects to retain whatever funds are raised, whether or not the goal is reached, sets it apart from other sites. So, our chances of actually being able to attend this important meeting are much greater this way! The money that we raise will be used to pay for the flights between Athens and Chicago, accommodation in Chicago, and registration to attend the conference.
The Society for Neuroscience Annual Meeting is a very important conference in the Neuroscience community. It offers a tremendous opportunity to share our results with the leaders in the field, as well as get valuable feedback to help guide our ongoing work. Plus, we get to hear and see about new findings and directions from other labs, and opens the possibility of starting new collaborations to help collectively advance Parkinson’s disease research!