The motility of Dictyostelium, a humble slime mould that lives in soil, has been keeping the research group led by Peter van Haastert going for some 30 years. It’s basic research, but over the last year the fungus has become a model system for Parkinson’s Disease.
This is the story of how studying the movement of a slime mould led to a discovery about the human movement disorder Parkinson’s Disease. And it is also about how a tiny change in a very big protein has enormous implications.
The story began with Dictyostelium, a bacteria-eating slime mould that lives in soil and can move around. Cell biologist Peter van Haastert has devoted his career to studying how it does this. In the process, he discovered a family of 11 closely related proteins, called Roco1 to Roco11. ‘We described this family in 2003, and noted that mammals have two related genes, called LRRK1 and LRRK2’, explains Van Haastert.
The paper didn’t have much of an impact. ‘In fact, it was quite difficult to get it published.’ All this changed in 2005, when it became clear that mutations in LRRK2 were the main cause of late-onset Parkinson’s Disease: ‘Suddenly our 2003 paper became quite important.’
The LRRK2 protein is difficult to study, but looks very similar to Roco4 from Dictyostelium. ‘So we used that to study the structure of the protein and the effect of a mutation that is frequently found in Parkinson’s patients.’ One famous patient is Back to the Future film star Michael J. Fox, who funds research into Parkinson’s Disease through his Michael J. Fox Foundation.
Together with Fred Wittinghofer (a colleague from Dortmund, Germany) and Arjan Kortholt from his own lab, Van Haastert received a grant from the Michael J. Fox Foundation to work on the Roco4 protein. Now the results have been published in the scientific journal Proceedings of the National Academy of Sciences.
The two research groups resolved the protein structure and noticed the change that the mutation made. ‘It’s really small’, says Van Haastert. One amino acid (proteins are long chains of 20 different types of amino acids) was replaced by another due to the mutation. As all proteins are folded, a bit like a twisted and clumped piece of string, different parts of the amino-acid chain are in close contact, and the new amino acid that was introduced by the mutation just happened to stick to an amino acid that was in close proximity. They formed what is called a hydrogen bond, something the original amino acid didn’t do.
‘The result is that the two amino acids sticking together more or less lock the protein, whereas it could move more freely with the original amino acid.’ In other words, the protein is locked in the ‘on’ position.
Roco4 is an enzyme, a protein that mediates a chemical reaction in the cell. And this reaction leads to the activation of other proteins. Because of the mutation, it turns off more slowly than usual, and the processes it activates become over active. ‘We don’t know yet which processes they are, but in LRRK2 they kill off the affected brain cells’, says Van Haastert.
So, by studying a mould, the Van Haastert group has found the cause of some cases of Parkinson’s Disease. And finding the cause is the first step towards finding a cure. ‘There are small molecules which will attach to the LRRK2 enzyme in exactly the right place, and turn it off again’, Van Haastert explains. His group tested one such molecule and it can block Roco4 in Dictyostelium.
But the road to a cure for people like Michael J. Fox is a long one. A drug that will switch off the mutated LRRK2 enzyme must be safe, it shouldn’t affect other enzymes, and it has to be able to reach the affected brain cells. ‘There’s a similar “simple” mutation which locks a gene called ras in the “on” position, which causes cancer. But despite decades of research and the investment of millions, we still can’t switch it off again.’
The Van Haastert group will be searching for the pathway activated by Roco4/LRRK2 to find out what it is that eventually kills the brain cells in patients with Parkinson’s Disease. There’s still a lot of work to do.
Most of the practical work in the study described was done by Bernd Gilsbach and Arjan Kortholt from the Van Haastert group, and Ingrid Vetter from the Dortmund group.
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