How does alpha-synuclein spread in Parkinson’s?
We know that alpha-synuclein plays an important role in Parkinson’s but researchers are still unclear how it causes nerve cell death across the brain and spinal cord. We take a look at the latest research into the troublesome protein.
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Quick overview if you’re in a hurry
- The shape of different proteins allows them to carry out different jobs in the cell.
- Proteins with the wrong shape can cause problems.
- In Parkinson’s, a protein called alpha-synuclein misfold, becoming toxic
- This toxic protein can travel from cell to cell and is believed to be responsible for spreading Parkinson’s through the brain.
- Understanding how it spreads is helping researchers discover ways to stop Parkinson’s in its tracks.
The building blocks of life
Before we can discover how proteins are involved in the spread of Parkinson’s, first we need to understand what proteins are and why they have different shapes.
Proteins are the building blocks of the cell and are responsible for growth, development and everyday tasks that keep our cells healthy. To do their jobs properly inside cells, proteins must first fold themselves into the correct shape. Much like the way a cardboard box must be folded to be able to hold its contents or a paper aeroplane has to be the correct shape to fly.
For example, collagen, a fibrous protein that provides structural support to cells is long and thin, with different chains of the protein wrapping around each other much like the fibres of a rope. The result is a flexible protein that can resist being pulled — perfect for its role in connective tissue. In comparison, enzymes (proteins that build up or break down other molecules in the cell) tend to be quite rounded (globular) in shape. This allows pockets to form that have a specific shape. ensuring that the enzyme only interacts with the molecules it’s meant to, like the way the right key can fit a lock.
To maintain their specific shape, proteins are folded in a certain way, held together by different chemical bonds. Disrupt these bonds and you change the shape of the protein. In some cases, this can be beneficial, such as the way a perm can be used to make hair curlier.
But in most cases, changing the shape of the protein is catastrophic and will mean that protein no longer works and has to be recycled.
When proteins become a problem
Protein misfolding is common in neurodegenerative conditions, including Alzheimer’s, Parkinson’s and Huntington’s. In addition to putting extra strain on the cell’s recycling systems, misfolded proteins can also start to form protein clumps. These clumps, also known as aggregates, can quickly become toxic to cells, making it harder and harder for them to work properly, and eventually causing cell death.
In Parkinson’s, the main culprit seems to be alpha-synuclein, a protein which first attracted attention in 1997. At this time, researchers were studying a family in Italy, where many members had been diagnosed with Parkinson’s. They found many members of the family had inherited an extremely rare changes in a gene called SNCA, which encodes the alpha-synuclein protein. In the same year, another study showed that alpha-synuclein was a major component of Lewy bodies, clumps of protein that are found inside the brains of people with Parkinson’s.
Alpha-synuclein was now well and truly implicated in the cause and spread of Parkinson’s.
Why is alpha-synuclein such a problem?
So what do we know about this problem protein? Well, despite decades of research, it’s still unclear what alpha-synuclein normally does in the cell. It’s thought that the protein may play a role in helping brain cells to send messages to other brain cells, but it may be involved in several other activities too.
Turning toxic
No-one is quite sure what causes alpha-synuclein to start clumping in brain cells in Parkinson’s, though recent research suggests that it might be mistakenly cut in Parkinson’s, causing it to start clumping.
What we do know for sure is that the trouble starts when alpha-synuclein changes from its usual helix shape into a sheet-like shape, making it more ‘sticky’ and more likely to clump.
A small number of these damaged proteins stick together to form a small toxic bundle called an oligomer. These oligomers of alpha-synuclein then clump together further, forming fibres of damaged alpha-synuclein knotted together.
The knotted fibres of alpha-synuclein then combine to form dense clumps of alpha-synuclein — the Lewy bodies that characterise Parkinson’s.
A disruptive presence
There’s much debate among the scientific community about what makes alpha-synuclein toxic to the brain cells.
For many years, it was assumed that Lewy bodies were toxic, stopping the cell from working properly and eventually causing it to die. But recent research suggests that Lewy bodies may actually be protective for nerve cells and it’s the smaller oligomers that are toxic. In fact, Lewy bodies may be the good guys, forming to sequester the oligomers away from the rest of the cell.
This idea was supported by a study in 2012, where researchers examined post-mortem sections of brains from people with Parkinson’s. They found that many of the dysfunctional or dying brain cells did not contain Lewy bodies. Another study showed that Lewy bodies are present in the brains of around 10% of people over 60 who do not have Parkinson’s.
And studies in cells have shown that alpha-synuclein oligomers are toxic — creating problems with all aspects of the cell, including signalling, recycling and energy production. So how does this protein end up causing a neurodegenerative condition?
The spread of Parkinson’s
Parkinson’s is different for everyone. But for most, more symptoms appear over time.
This suggests that Parkinson’s spreads as it progresses, affecting different parts of the brain that are responsible for the various motor and non-motor symptoms that are associated with the condition.
This idea was brought to life in 2003 by a german anatomist Heiko Braak, who published a paper detailing the proposed spread of Parkinson’s throughout the brain. Braak and his team worked out the predicted spread of Parkinson’s by following the pattern of Lewy bodies in the brain, beginning in the lower brainstem and working its way through the brain out to the cortex.
The spread of alpha-synuclein
So the question becomes, how does Parkinson’s spread through the brain? Suspicion has fallen on alpha-synuclein itself.
In the 1980s, some people with Parkinson’s had nerve cells transplanted into their brains as a potential treatment. Years later, their brains were examined post-mortem. It was found that the transplanted nerve cells contained Lewy bodies, suggesting that alpha-synuclein can move between cells, spreading throughout the brain. This led to the surprising idea that alpha-synuclein may act like a prion protein.
A prion-like protein
A prion is a protein that has the ability to spread by making other proteins in the brain misfold. Prions are responsible for several brain diseases, the most famous of which is mad cow disease. And recently, researchers have discovered that neurodegenerative conditions, such as Alzheimer’s, Parkinson’s and Multiple System Atrophy may also have a prion-like component to them.
In Parkinson’s, studies in cells have shown that misfolded alpha-synuclein can encourage other molecules of alpha-synuclein to misfold. And in mice, injecting mis-shapen alpha-synuclein into the brain caused Lewy bodies to form and dopamine-producing nerve cells to die. Within 6 months of the injection, movement, strength and balance were affected.
Crucially, nerve cells connected to those near the injection site also developed Lewy bodies — suggesting that the alpha-synuclein was moving from cell to cell.
But for alpha-synuclein to be responsible for the progression of Parkinson’s, it needs to be able to travel from an affected cell into neighbouring cell progressively “infecting” the brain.
And with researchers discovering that the original alpha-synuclein clumps may originate in the gut or in olfactory bulb, the small structure in our heads responsible for our sense of smell, understanding how exactly this protein spreads between two cells may shine a light on ways to stop it ever reaching the brain at all.
Leaving the cell
Research has shown there could be two very different ways for toxic forms of alpha-synuclein to leave the cell — either by breaking out, or by sneaking out the front door.
A groundbreaking study in 2017 found that oligomers of alpha-synuclein were able to insert into and puncture the membranes of cells. The cell membrane is like a balloon and plays a vital role in keeping the contents of the cell together and protected. The researchers found that when the membrane was punctured by alpha-synuclein, it had dire consequences — causing the contents of the cells to leak out, eventually leading to cell death.
The death of the cell isn’t the only way alpha-synuclein can escape. Research has shown that brain cells affected in Parkinson’s ‘leak’ alpha-synuclein. This seems to happen when the cell’s ‘waste disposal’ centre is not working correctly, leading to a build-up of abnormal alpha-synuclein clumps which eventually escape from the cell. Structures called ‘exosomes’ may be the vehicles that allow alpha-synuclein to escape the cell. Exosomes are like small capsules that are released by cells. Their usual role is to help the cells communicate with their neighbours, shuttling various molecules from one cell to another. Recent research has shown that alpha-synuclein interacts with another protein called hsc70, which helps it ‘stow away’ inside exosomes, effectively allowing alpha-synuclein to leave the cell via a letter box in the front door.
Entering the neighbouring cell
Once out of one cell, the toxic alpha-synuclein now has the job of getting into the neighbouring cells. Researchers have identified different ways it could do this.
The rogue protein could be taken up the cell in a process called “endocytosis”, where it merges with the cell membrane and enters the cell. Molecules that enter this way are normally then sent to the “sorting station”, where the cell decides what to do with them. But researchers think that alpha-synuclein is able to break away from this pathway and wreak havoc in the rest of the cell.
New research also suggests that alpha-synuclein can hitch a lift with proteins used to create channels in cell membranes. Nerve cells lying close to each other can create small tunnels, known as gap junctions, that allow them to communicate with each other. It was originally suggested that maybe alpha-synuclein could spread between cells using these channels, but the toxic clumps would be too big. Instead, researchers in Sweden looked at the proteins that make up these channels, called connexins. They found that aggregates of alpha-synuclein could bind to a specific connexin and hitch a lift into the cell.
Finally, in an unexpected twist of fate, researchers have also found a direct link between the alpha-synuclein protein and other prion proteins. Studies in mice found that prion protein could help misfolded alpha-synuclein get into cells, helping it spreading across the brain. Strangely, the clumps of alpha-synuclein then seem to block the spread of the prion protein. More research is needed to fully understand the relationship between these two troublesome proteins.
Stopping the spread to stop Parkinson’s
Given all this evidence, it’s perhaps not surprising that researchers have been focusing on how to stop the spread of misfolded alpha-synuclein. And progress has already been made turning understanding into potential treatments — indeed a number of anti-alpha-synuclein based therapies have already entered clinical trials.
What is clear is that there’ll be more alpha-synuclein research news on the horizon, and we’ll be keeping our eye on developments.
