̽��ֱ�� of Cambridge - Giuliana Fusco

Function identified of ‘mystery protein’ that kills healthy brain cells of people with Parkinson’s

Anonymous — Wed, 10 Feb 2021 07:38:42 +0000

A study published in Nature Communications presents new evidence about what a key protein called alpha-synuclein actually does in neurons in the brain.

Dr Giuliana Fusco from the ̽��ֱ�� of Cambridge, and lead author of the paper, said: “This study could unlock more information about this debilitating neurodegenerative disorder that can leave people unable to walk and talk. If we want to cure Parkinson’s, first we need to understand the function of alpha-synuclein, a protein present in everyone’s brains. This research is a vital step towards that goal.”

Parkinson’s disease is a progressive neurological disorder that causes nerve cells in the brain to weaken or die. ̽��ֱ��disease has a variety of symptoms including tremors – particularly in the hands – gait and balance problems, slowness and extreme stiffness in the arms and legs. Parkinson's develops when cells in the brain stop working properly and can’t produce enough dopamine, a chemical that controls movement in the body by acting as a messenger between cells.

̽��ֱ��disease mostly affects people over 60 and gets worse over a number of years but early-onset Parkinson’s can affect people even younger.

More than 10 million people worldwide live with Parkinson’s disease, including actor Michael J Fox who was diagnosed aged 29, singer Neil Diamond, comedian Billy Connolly and musician Ozzy Osbourne. Parkinson’s can affect women, but men are more likely to have the disease.

It is not yet known why people get Parkinson's, but researchers think it's a combination of age, genetic and environmental factors that cause the dopamine-producing nerve cells to die affecting the body’s ability to move.

This study looked at what was going on inside healthy conditions to help pinpoint what is going wrong in the cells of people with Parkinson’s. All cells in the body have a plasma membrane that protects cells and usually transports nutrients in and clears toxic substances out.

“One of the top questions in Parkinson’s research is: what is the function of alpha-synuclein, the protein that under pathological conditions forms clumps that affect motor and cognitive abilities," said Fusco, who is also a research Fellow at St John's College, Cambridge. “Usually you discover a protein for its function and then you explore what is going wrong when disease strikes, in the case of alpha-synuclein the protein was identified for its pathological association but we didn’t know what it did in the neuron.

“Our research suggests that the alpha-synuclein protein sticks like glue to the inner face of the plasma membrane of nerve cells but not to the outer– a crucial new piece of information.”

̽��ֱ��research was predominantly carried out at the Cambridge Centre for Misfolding Diseases within the ̽��ֱ��'s Yusuf Hamied Department of Chemistry. ̽��ֱ��scientists used synthetic models to mimic brain cell membranes during the study.

“When this protein is functioning normally it plays an important part in the mechanisms by which neurons exchange signals in the brain," said co-author Professor Alfonso De Simone, from Imperial College London. "But it has a dark side because it malfunctions and begins to stick together in clumps which eventually spread and kill healthy brain cells. Our research showed that this protein clings onto the inner face of the plasma membrane of brain cells so we are slowly building a picture of this very complex disorder by studying the key function of alpha-synuclein.”

There are treatments and drugs available to Parkinson’s patients and the disease isn’t fatal, but nothing is available to reverse the effects of the disease. Introducing lifestyle changes including getting more rest and exercise can also alleviate symptoms.

De Simone said: “We have thousands of proteins in our bodies and until the function of this mystery protein is confirmed with more research, drug therapies cannot begin to be developed to tackle the origins of Parkinson’s Disease in case medication accidentally affect a crucial purpose of the alpha-synuclein protein.”

Reference:
Wing K Man et al. ' ̽��ֱ��docking of synaptic vesicles on the presynaptic membrane induced by α-synuclein is modulated by lipid composition.' Nature Communications (2021). DOI: 10.1038/s41467-021-21027-4

Adapted from a St John's College press release.

Scientists have made a ‘vital step’ towards understanding the origins of Parkinson’s disease – the fastest growing neurological condition in the world.

If we want to cure Parkinson’s, first we need to understand the function of alpha-synuclein, a protein present in everyone’s brains.

Giuliana Fusco

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Parkinson’s Disease protein plays vital “marshalling” role in healthy brains

tdk25 — Mon, 19 Sep 2016 09:00:00 +0000

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. ̽��ֱ��new study, carried out by researchers at the ̽��ֱ�� 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, ̽��ֱ�� 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.”

̽��ֱ��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.”

̽��ֱ��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.”

̽��ֱ��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.

̽��ֱ��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.

̽��ֱ��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.

̽��ֱ��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.”

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

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

Alfonso De Simone

̽��ֱ��study suggests that alpha-synuclein acts as a bond between cellular transporters in healthy brains, regulating their flow and therefore controlling the signalling process.

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