In addition to LRRK2, my lab has been working on some of the less well studied ROCO proteins for a number of years now (see our previous paper on DAPK1). In collaboration with Elisa Greggio and her lab over in Padova, Sybille Dihanich has been investigating MASL1, which is the smallest of the human ROCO proteins. What Sybille found is quite intriguing. MASL1 forms a series of complexes, and the nature of those complexes is dependent upon different Guanosine nucleotides binding to the active site of the protein. Although MASL1 has a very different sequence to LRRK2, we think that looking at the biology of this protein might help us gain a greater understanding of LRRK2 biology.
Read about Sybille’s research at FEBS Journal:
Following my move to the University of Reading, there has been a bit of a changing of the guard, so I thought I would take this opportunity to look back on the last six years and wish everyone well for the future. We recently had a lunch at the magnificent Hare and Tortoise in the Brunswick centre (for those not familiar with the Hare and Tortoise, it is like Wagamamas but with knobs on) to celebrate a couple of papers going out and folk moving on. Adam (who has been doing postdoctoral research with myself and Rina Bandopadhyay at the Queen Square brain bank for the last few years) brought along his Canon-A1 camera, the product of which is below. Adam has just started a new job over at the National Institute of Health in Bethesda – so all the best for that Adam! Claudia is still plugging away at LRRK2 in the UCL labs, while Jack (who is doing a PhD with Rina) is coming to the end of his studies and is moving on to pastures new, and Sybille is exploring the world outside of research.
Left to right: Rina Bandopadhyay, Claudia Manzoni, Sybille Dihanich, Adamantios Mamais, Patrick Lewis and Jack Brelstaff
When mutations in LRRK2 linked to Parkinson’s disease were first described back in 2004, an immediate question was whether there might be similar mutations in the paralogous protein LRRK1 – a protein that shares many of the features of LRRK2. Thus far, this does not seem to be the case, although it is not an issue that has been looked at in detail for a number of years. Eva Schulte and Juliane Winkelmann, neurologists based in Munich, have been looking at coding variations in LRRK1 and risk of developing Parkinson’s disease in a series of families that they have been seeing in clinic. We worked with them to look at some of the biological properties of these variants, expressing them in cells. Based upon these genetic and cellular studies, there is some evidence that rare variants in LRRK1 can increase risk for PD, but this study really highlights the difficulties in interpreting the role of rare coding changes in disease. For sure, this is an issue that needs a lot more research before we have a definitive conclusion.
Read more about this study in Eva’s article in Neurogenetics:
As a break from the normal science related posts on the blog, I thought I would post about some of my extracurricular efforts. Last weekend I took part in the Scullers Head on the Thames in London. For those who aren’t familiar with the Scullers Head, it is raced over the same course as the Oxford/Cambridge Boat Race (just about 5 miles) – but without seven other people in the boat to help you out or a small person sitting in the stern shouting at you to go faster. Definitely in the top five most painful things I have done when the return trip from Putney (where the race finished) to Mortlake is taken into account. Photo below.
In a new paper from the lab, Claudia Manzoni studies how fibroblast cells from people with Parkinson’s disease caused by mutations in LRRK2 react to starvation. Although the changes are quite subtle, there are differences between the way that fibroblasts that contain mutant LRRK2 respond to being starved – suggesting that there may be changes in the way that these cells regulate a key process called autophagy (a term which comes from the greek meaning to eat yourself, and is one of the ways that cells get rid of waste and recycle proteins and organellles). One important bit of information that comes out of this study is that all of the mutations that Claudia looked at, no matter where in the LRRK2 protein they are found, seem to have a similar impact on autophagy. This is important because, up until now, there hasn’t been a clear cellular symptom linked to all these mutations and might indicate that disrupted autophagy is a common feature of LRRK2 mutations. A lot more work is needed in order for us to really understand how mutations in LRRK2 alter autophagy, but this study provides an intriguing hint that autophagy might be very important in Parkinson’s disease.
Read more about our study at Biochemical and Biophysical Research Communications:
On Wednesday (the 6th of November) I went up to Harlow to give a short talk to the Harlow Parkinson’s UK branch on how genetics is helping us to understand Parkinson’s disease. I got a bit damp cycling to the meeting from the station, but was soon warmed up by the welcome and tasty lunch provided by the branch. As always I was very impressed by the questions from the patients, family members and carers at the talk, and hopefully those who attended got an insight into some of the research that my group and others are carrying out. Many thanks to Tony Wells for inviting me up to Harlow!