Excess quantities of a specific
protein in the brain dramatically increase the chances of so-called “nucleation
events” that could eventually result in Parkinson’s Disease, according to a new
study.
Finding a cure for Parkinson’s depends on our
ability to understand it. For the first time, we have been able to provide a
mechanistic description of the initial, molecular events that can ultimately
result in the development of the disease
Celine Galvagnion
The circumstances in which a protein closely
associated with Parkinson’s Disease begins to malfunction and aggregate in the
brain have been pinpointed in a quantitative manner for the first time in a new
study.
The research, by a team at the University of Cambridge,
identified a critical threshold in the levels of a protein called
alpha-synuclein, which normally plays an important role in the smooth flow of
chemical signals in the brain.
Once that threshold is exceeded, the researchers
found that the chances that alpha-synuclein proteins will aggregate into
potentially toxic structures are dramatically enhanced. This process, known as
nucleation, is the first, critical step in the chain of events that scientists
think leads to the development of Parkinson’s Disease.
The findings represent another important step
towards understanding how and why people develop Parkinson’s. According to the
charity Parkinson’s UK, one in every 500 people in the UK – an estimated
127,000 in all – currently has the condition, but as yet it remains incurable.
Dr Celine Galvagnion, a Research Associate at St
John’s College, University of Cambridge, and the lead author of the study,
said: “Finding a cure for Parkinson’s depends on our ability to understand it.
For the first time, we have been able to provide a mechanistic description of
the initial, molecular events that can ultimately result in the development of
the disease.”
The study suggests that the likelihood of an
individual developing Parkinson’s is related to a delicate balance between the
protein, alpha-synuclein, and the number of synaptic vesicles in their brain.
Synaptic vesicles are tiny, bubble-like structures that help to carry
neurotransmitters, or chemical signals, between nerve cells. The cell
constantly reproduces the vesicles to enable this.
Under normal circumstances, alpha-synuclein plays
a pivotal role in the release of these neurotransmitters from one nerve cell to
another. It does this by attaching itself to a thin membrane around the
synaptic vesicle, known as the lipid bilayer.
When alpha-synuclein binds to lipid vesicles, it
folds into a helical shape in order to perform its function. In certain
circumstances, however, the proteins on the vesicle surface misfold and stick
together. Once this nucleation process has begun, there is then a danger that
free protein molecules within the brain cell will come into contact with the
misshapen nucleus on the lipid surface. As these combine, they form thread-like
chains, called amyloid fibrils, and start to become toxic to other cells. These
amyloid deposits of aggregated alpha-synuclein, also known as Lewy-bodies, are
the hallmark of Parkinson’s Disease.
Previous research has suggested that
overexpression of alpha-synuclein in the brain is somehow associable with the
onset of Parkinson’s, and that the interaction of alpha-synuclein with the
lipid bilayer could play a role in modulating the development of the disease,
but until now it was not clear why this might be the case.
In the new study, the research team simulated the
process by which the proteins attach themselves to the vesicles by creating
synthetic vesicles in the lab. These were then incubated with different
quantities of alpha-synuclein.
The results showed that when the ratio of protein
molecules to vesicles exceeds a level of about 100 (a level 10 times higher
than that typically found in a human brain), the proteins attaching themselves
to the lipid bilayer around a vesicle are too highly concentrated and bunch
together on the surface. As a result, the chances of proteins nucleating on the
lipid surface are, remarkably, at least a thousand times higher than the
chances of two proteins randomly binding together in solution.
“It became clear in our experiment that there are
specific conditions in which you can see the aggregation happening, and other
conditions in which you don’t,” Galvagnion added. “It turns out that the ratio
determines the ability of alpha-synuclein proteins to nucleate. This provides
us with a likely explanation of how the initial steps leading to Parkinson’s
occur.”
Together, the results provide, for the first
time, a mechanistic description of the key role that membrane interactions can
play in the initiation of neurodegenerative diseases, including Parkinson’s
Disease.
The full report appears in the new issue of Nature
Chemical Biology.
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