Digging for a cure at the Oxford Parkinson’s Disease Centre (OPDC)
What is scientific research?
Imagine you travel to a field in the middle of the countryside. You've been told there is something buried in the field; something valuable beyond words, like a cure for Parkinson's. The problem is, you don't know where in the field the cure resides or how deep you will have to dig for it. You also don't know what a cure will look like. You stand in the middle of the field trying to decide where to start. How do you find a cure for Parkinson's?
You gather a team of expert diggers and based on what other researchers have found in nearby fields (and for other diseases) you choose an area in the middle of the field. You start digging and go through several layers of soil. As you dig you analyse the components of the soil for any traces of the cure. That's the difficulty of scientific research; because you are attempting to uncover something hidden from view you only have knowledge from previous layers of soil to go on; you try to make sure as far as you can that the particular part of the field you are currently studying will hold the vital clue to where to dig next, or how far you will have to dig down to get to a cure.
What is the OPDC?
I arrived at a particular part of the Parkinson's research field when I visited the lab of Dr Richard Wade-Martins at the Oxford Parkinson's Disease Centre (OPDC). The OPDC is an interdisciplinary research centre, which means that clinicians (investigating better ways to diagnose and treat Parkinson's), brain scientists (investigating the nerve cell networks that go wrong), cell biologists (investigating what goes wrong in cells) and, linking these approaches together, mouse geneticists (investigating Parkinson's in mice) are under one roof. This ensures the links between human patients and the knowledge generated from cells, nerve cell networks and model organisms is as close as possible. In other words, they are busying digging in multiple parts of the Parkinson's field and increasing the chances of finding that vital clue.
From Skin cells to Nerve cells - Induced pluriopotent stem cells (IPSCs)
Dr Wade-Martin's lab investigates cells and mouse models of Parkinson's. The first part of the field I was shown contained some amazing biology. Researchers in the lab know enough to take skin cells from human patients and convert these into nerve cells, which are the same as those cells that go wrong in Parkinson’s affected brains. I will just let that sink in. Look at your skin...the tissue that covers your body can be changed into nerve cells! Amazing! These cells are incredibly valuable because they contain all the genetic changes (known and unknown) that cause Parkinson's. Therefore, understanding and treating what goes wrong in these nerve cells will give a more comprehensive view of what goes wrong in Parkinson’s. Studies using these cells will be a huge leap forward in understanding and treating human patients.
LRRK2 and its role in Autophagy
One of the genes known to cause Parkinson's is LRRK2. Sergey Brin, one of the founders of Google, has a mutation in this gene and therefore has an increased chance of developing Parkinson's. LRRK2 normally passes messages to other proteins in the cell (in a game of Chinese whispers called phosophorylation) and these proteins carrying out processes in the cell; LRRK2 is sort of the manager in a factory. In Sergey Brin’s brain (and other affected by Parkinson’s), LRRK2 becomes hyperactive and gives out messages to everyone, causing chaos; cells normally work by keeping calm and balanced.
LRRK2 has been implicated in a process called autophagy. Imagine the cell is a chemical factory, producing vital chemicals to make sure the cell functions properly. However, like a real chemical factory it produces waste products. Autophagy is the process whereby the cell cleans up after itself and chucks away the rubbish it generates. Mutations in LRRK2 can disrupt the cleaning regime of the cell; eventually accumulated rubbish makes the cell become chaotic and it does not function properly. Eventually the cell begins to malfunction and it dies, therefore causing a reduction in dopamine levels and the symptoms of Parkinson’s.
Work in the lab is trying to discover which part of autophagy LRRK2 controls; is it when the cell is preparing to clean (induction), getting the bin bags ready (autophagosome formation), picking up the rubbish (lysosome fusion) or throwing the bin bags away (autophagosome breakdown). A neat experiment is being used to work out where LRRK2 is affecting this process. There are proteins that give off specific coloured light (e.g. green). These can be expressed in cells and seen under a microscope; to provide a contrast, the rest of the cell is labelled red with a chemical. At the start of the process of autophagy the coloured protein will give off green light but at the end when the protein is picked up ready to be thrown out the protein no longer produces green light (due to the acidic environment of the autophagosome). Therefore, in LRRK2 mutant cells from patients the proportion of green to red will tell you where the process has stopped; more green means mutant LRRK2 has stopped the process early and conversely more red means it stops it late in autophagy. This is important to know because it tells us which drugs to potentially use to correct the process.
Another major gene implicated in Parkinson's is alpha synuclein; alpha synuclein protein clumps together to form Lewy bodies in Parkinson's affected cells. Dr Wade-Martins lab published some work this year (PNAS 110 e4016) showing they created a mouse with three copies of the alpha synuclein gene (normally mice have one copy). This forces the cell to make 3x the amount of alpha synuclein protein; Lewy body formation (common in Parkinson’s) is therefore more likely in these mice. Indeed these mice show symptoms of late-onset Parkinson’s. There are humans who also have three copies of the alpha synuclein gene and develop Parkinson’s. Members of the lab have been trying to use drugs to break up the Lewy bodies, prevent cell death and stop Parkinson’s from developing. It is early days but this work demonstrates the benefit of having multiple specialists in the same research centre: cell work can lead to mouse work which can lead to testing drugs to stop what is happening in the cells of the mouse, and ultimately human sufferers.
After my visit to the OPDC I gained renewed hope that one day soon the crucial piece of soil in the Parkinson’s field will be lifted to reveal a cure for this devastating disease.