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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