Understanding alpha-synuclein— nearly 30 years of research with Professor Maria Grazia Spillantini

The misfolding protein in Parkinson’s

Proteins are the building blocks of the cells. They each have a role to make sure that the processes in the body work properly and fold in a certain way to do their job. When proteins don’t fold in the correct way, they can’t do their job properly.

In Parkinson’s, the main protein that misfolds is alpha-synuclein. Sticky clumps of alpha-synuclein, called Lewy bodies, form in cells and cause damage in a region of the brain called the substantia nigra.

Misfolded alpha-synuclein in one cell triggers other alpha-synuclein to start misfolding too, within the cell and then in other surrounding cells. This adds to the build-up of waste inside cells, eventually leading to the loss of the brain cells that produce dopamine.

As brain cells die, less dopamine is produced and released. This loss of dopamine is what causes the over 40 symptoms of Parkinson’s.

Where does the journey begin?

Researchers have been studying alpha-synuclein for decades to find out more about how it is involved with Parkinson’s. Improving our understanding can help lead to new ways to target it, and treat the symptoms of Parkinson’s or slow down the progression of the condition.

Research into alpha-synuclein’s involvement in Parkinson’s has been going on for decades and our knowledge of it has greatly advanced. One of the researchers who has pioneered the research into alpha-synuclein is Professor Maria Grazia Spillantini, who led the work that uncovered alpha-synuclein in Lewy bodies in Parkinson’s in 1997.

Professor Maria Grazia Spillantini

Professor Spillantini was born in Italy and has worked at the University of Cambridge since 1987. She is now Professor of Molecular Neurology in the Department of Clinical Neurosciences at the University of Cambridge.

In 1997, Maria Grazia was part of a team looking more closely at Lewy bodies, seen in the brain tissue of people with Parkinson’s. Her work uncovered that those clumps were made up of alpha-synuclein.

At around the same time, another research group was looking closely at a family where many generations had developed Parkinson’s. They found one gene that appeared different in all those family members: the gene that provides the instructions for making alpha-synuclein.

This was just the start of Maria’s journey to learn more about how Parkinson’s develops. Over the past couple of decades, Maria Grazia and her research teams have worked to find out more about alpha-synuclein.

This discovery opened up many avenues of research and has advanced our understanding of what might be happening in Parkinson’s. Maria has continued her research through multiple projects funded by Parkinson’s UK which have taken us closer to getting the answers we need. Her lab is now made up of a team of 11 all focusing on the development of neurological conditions such as Parkinson’s.

A brief history of Maria Grazia’s research into alpha-synuclein in Parkinson’s

The below shows some of the research Maria Grazia has been involved in, and the key milestones in research that have improved our knowledge of alpha-synuclein and Parkinson’s.

1994: Identifying the protein alpha-synuclein

Maria Grazia and her collaborators Michel Goedert and Ross Jakes identified two proteins in the human brain that they named alpha-synuclein and beta-synuclein. She then identified which genes code for these proteins and named them SNCA for alpha-synuclein and SNCB for beta-synuclein. Their research suggested that alpha-synuclein could be involved in the process of sending messages between brain cells.

1997: What are Lewy bodies that are found in Parkinson’s made of?

Maria Grazia was part of a team studying Lewy bodies that are present in the cells of people with Parkinson’s and Lewy body dementia. They thought alpha-synuclein may be present in Lewy bodies. To confirm this, they used a research tool called an antibody, designed to stick to alpha-synuclein in cells and colour it, so it can be seen more clearly through a microscope.

Looking at brain tissue from people with Parkinson’s and people with Lewy body dementia they found that lots of the coloured alpha-synuclein neatly overlapped with the Lewy bodies in people with both conditions. This showed that Lewy bodies were made up of clumps of alpha-synuclein.

1998: Is alpha-synuclein the only part of the clumps you find in the Lewy bodies?

The clumps in the Lewy Bodies were made up of lots of filaments, which are long and thin fibres, tangled together. Maria Grazia and her collaborators showed that these filaments were made up of only alpha-synuclein and no other proteins were mixed in.

2006: Using mice to understand how alpha-synuclein sticks together

Previous research had suggested that Lewy bodies contain a mutated version of alpha-synuclein, which is shorter than usual and that these short versions of alpha-synuclein clump and stick together more easily. They wanted to see what effect these short versions had on the substantia nigra, the area of the brain that is most affected in Parkinson’s, as well as any other areas.

For this research, Maria Grazia’s team developed a mouse model to investigate. A vital part of lab-based research involves studying complete living systems with the conditions. The mouse models are able to replicate many aspects of Parkinson’s to study how the condition may develop and progress in humans. Any research that involves living organisms is tightly regulated.

Read our policy on using animals in research.

During the study, the team found that in the mouse brain, these mutated forms of alpha-synuclein clump together more easily. They also found that it was harder to break the clumps down into waste products and remove them from the nerve cells in the brain, where they kept building up.

Not only did the clumps affect the substantia nigra, but also other areas which are associated with decision making, motor control, emotions and smell. This could help explain some of the non-motor symptoms that are associated with Parkinson’s.

2010: How do clumps of alpha-synuclein affect brain cells?

Further research in mouse models in Maria Grazia’s lab investigated how clumps of alpha-synuclein may disrupt communication between brain cells, reduce the amount of dopamine that is released and cause brain cells to die. Brain cells communicate with each other by sending chemical messages from an area called the synapse.

Maria Grazia and her team found that the accumulation of clumps of alpha-synuclein in the synapse caused them to release less dopamine. The sticky clumps also caused other proteins in the cells to move around and settle in the wrong places. This might be another reason that the brain cells stop working properly, and cause brain cells to die.

2019: How could a new drug, called anle138b, be used to treat Parkinson’s?

Maria Grazia’s team developed a new mouse model that progressively develops clumps of alpha-synuclein in brain cells. This is more representative of what’s going on in the brains of people with Parkinson’s. Over time, there is a reduction in dopamine release from the synapse which is followed by a progressive loss of brain cells. And then the development of some of the symptoms seen in Parkinson’s in humans. The mouse models developed during this research can be used going forward to test future drugs for the treatment of Parkinson’s.

Anle138b is a drug that binds to clumps of alpha-synuclein. When it binds to the clumps, it dissolves them, breaking them up and preventing more clumps from forming. In the mice, anle138b restored a normal release of dopamine from the synapses, stopped brain cells from dying and eased motor symptoms.

The drug has now progressed to human trials and is being investigated for safety and efficacy in humans for treating Parkinson’s.

2022: Where do clumps of alpha-synuclein form, and where and how do they spread?

Previous research suggested that for the majority of people with Parkinson’s, alpha-synuclein may actually start to form in nerve cells in the gut, and travel to the brain via the vagus nerve. This might explain why some of the early symptoms of Parkinson’s can involve the gut, such as constipation.

For this study, Maria Grazia and her team have developed a mouse model which starts producing alpha-synuclein in the gut, and they will then follow its journey to see if alpha-synuclein in the gut can make its way to the brain.

They will also be looking at whether other factors, such as inflammation of the gut (colitis), which many people with Parkinson’s experience, could play a role in the development of Parkinson’s by facilitating the spreading of alpha-synuclein from the gut to the brain.

Read more about the role of the gut in Parkinson’s.

If we can confirm that alpha-synuclein clumps form in the gut before travelling to the brain, we can look at the gut as a potential for diagnosing and treating Parkinson’s earlier.

Further research

This is just a selection of the vast work that Maria Grazia has been a part of. Thanks to the dedication of researchers like her, we have a far better understanding of how alpha-synuclein might be a potential target for future treatments for Parkinson’s. Maria Grazia and her colleagues have also completed more research, including research into other misfolding proteins in conditions like dementia.

There is still a lot to learn about alpha-synuclein and its role in Parkinson’s. The more we know about it, the more we can research possible treatments targeting alpha-synuclein, which is why Parkinson’s UK is funding multiple research projects investigating alpha-synuclein.