Researchers have established how a
protein called alpha-synuclein, which is closely associated with
Parkinson's Disease, functions in healthy human brains. By showing how
the protein works in healthy patients, the study offers important clues
about what may be happening when people develop the disease itself.
Parkinson's Disease is one of a group of conditions known as "protein
misfolding diseases," because they are characterised by specific
proteins becoming distorted and malfunctioning. These proteins then
cluster into thread-like chains, which are toxic to other cells.
While malfunctioning alpha-synuclein has long been recognised as a
hallmark of Parkinson's Disease, its role in healthy brains was not
properly understood until now. The new study, carried out by researchers
at the University of Cambridge and Imperial College London, shows that
the protein regulates the flow of cellular transporters known as
synaptic vesicles -- a process fundamental to effective signalling in
the brain.
Significantly, the researchers also tested mutated forms of
alpha-synuclein that are linked to Parkinson's disease. This was found
to interfere with the same mechanism, essentially by impairing the
ability of alpha-synuclein to regulate the flow of synaptic vesicles,
and hence compromising the signalling between neurons.
Giuliana Fusco, a Chemistry PhD student from St John's College,
University of Cambridge, carried out the main experiments underpinning
the research. "It was already clear that alpha-synuclein plays some sort
of role in regulating the flow of synaptic vesicles at the synapse, but
our study presents the mechanism, explaining exactly how it does it,"
she said. "Because we have shown that mutated forms of alpha-synuclein,
which are associated with early onset familial forms of Parkinson's
Disease, affect this process, we also now know that this is a function
that may be impaired in people who carry these mutations."
The researchers stress that the results should be treated with
caution at this stage, not least because much about Parkinson's Disease
remains obscure.
Dr Alfonso De Simone, from the Department of Life Sciences at
Imperial, and one of the study's lead authors, said: "It is important to
be careful not to leap to conclusions. So much is happening in the
development of Parkinson's Disease and its origins could be multiple,
but we have made a step forward in understanding what is going on."
The precise function of alpha-synuclein has been the subject of
considerable debate, partly because it is abundant in red blood cells as
well as in the brain. This implies that it is a rather strange,
metamorphic protein that can potentially perform several different
roles.
Establishing that it regulates the mechanisms that enable signalling
to occur in the brain represents significant progress. "If you remove
part of a machine, you need to know what it is supposed to do before you
can understand what the consequences of its removal are likely to be,"
De Simone said. "We have had a similar situation with Parkinson's
Disease; we needed to know what alpha-synuclein actually does in order
to identify the right strategies to target it as a therapeutic approach
to Parkinson's."
The study involved lab-based experiments in which synthetic vesicles,
modelling the synaptic vesicles found the brain, were exposed to
alpha-synuclein. Using nuclear magnetic resonance spectroscopy, the
researchers examined how the protein organised itself structurally in
relation to the vesicles. To verify the findings, additional tests were
then carried out on samples taken from the brains of rats.
The basic process by which signals pass through the brain involves
neurotransmitters, which are carried inside the synaptic vesicles, being
passed across synapses -- the junctions between neurons. During
signalling, some vesicles move to the surface of the synapse, fuse with
the membrane, and release the neurotransmitters across the connection,
all in a matter of milliseconds.
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The researchers found that alpha-synuclein plays an essential part in
marshalling the vesicles during this process. Two different regions of
the protein were found to have membrane-binding properties that mean it
can attach itself to vesicles and hold some of them in place, while
others are released.
By holding some of the vesicles back, the protein essentially
performs a regulatory function, ensuring that neither too many, nor too
few, are passed forward at any given moment. "It is a sort of
shepherding effect by alpha-synuclein that occurs away from the synapse
itself, and controls the number of synaptic vesicles used in each
transmission," Fusco said.
The research suggests that in some familial cases of early onset
Parkinson's Disease, because alpha-synuclein malfunctions as a result of
genetic alterations, the protein's marshalling role is compromised. One
of the trademarks of Parkinson's Disease, for example, is an excess of
alpha-synuclein in the brain. In such circumstances, it is possible that
too much binding will take place and the flow of vesicles will be
limited, preventing effective neurotransmission.
"At this stage we can only really speculate about the wider
implications of these findings and more research is needed to test some
of those ideas," De Simone added. "Nevertheless, this does seem to
explain a large body of biochemical data in Parkinson's research
The study suggests that alpha-synuclein acts as a bond between cellular transporters in healthy brains, regulating their flow and therefore controlling the signalling process. This offers important clues about what may be going wrong when it malfunctions in Parkinson’s Disease.Credit: Alfonso De SimoneResearchers have established how a protein called alpha-synuclein, which is closely associated with Parkinson's Disease, functions in healthy human brains. By showing how the protein works in healthy patients, the study offers important clues about what may be happening when people develop the disease itself.Parkinson's Disease is one of a group of conditions known as "protein misfolding diseases," because they are characterised by specific proteins becoming distorted and malfunctioning. These proteins then cluster into thread-like chains, which are toxic to other cells.
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