Cambridge University. UK: 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.
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 from the Department of Chemistry 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 other members of the research group were Professor Chris Dobson (cmd44@cam.ac.uk),
Professor Michele Vendruscolo and Dr Tuomas Knowles. All are members of
the Centre for Protein Misfolding Diseases, which is based at the
University's Department of Chemistry. The full report appears in the new
issue of Nature Chemical Biology.
- See more at: http://www.cam.ac.uk/research/news/protein-threshold-linked-to-parkinsons-disease#sthash.rvuRhKUN.dpuf