Wednesday, 27 November 2013

Digging for a cure at the Oxford Parkinson's Disease Centre (OPDC) - Part Two

The role of LRRK2 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.

Treating alpha-synuclein?

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.

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