Researchers have identified how alpha-synuclein, the protein associated with Parkinson’s Disease, enables communication between neurons in the brain, offering important clues about what may be happening to patients when the protein malfunctions.

This is a process which may be impaired in people who carry mutations associated with early onset familial forms of Parkinson’s Disease

Giuliana Fusco

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.

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 paper, Structural Basis of Synaptic Vesicle Assembly Promoted by alpha-Synuclein, is published in Nature Communications. DOI: 10.1038/NCOMMS12563.

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