New knowledge about key mechanism underlying numerous brain disorders
Neuroscientists at Aarhus University have been able to prove how, under certain circumstances, the protein clumping key to several neurodegenerative disorders can develop into an unprecedentedly toxic and aggressive variant.
The Parkinson’s disease family has several members, and – to varying degrees – they share the same symptoms.
One of these diseases is MSA, multiple system atrophy, and like Parkinson’s disease it is a neurodegenerative disorder.
In both Parkinson’s and MSA, a specific protein plays the villain.
This protein is called alpha-synuclein, and in both diseases it forms “protein clumps” – so-called aggregates – which progressively attack and destroy key brain functions.
However, there are some differences between Parkinson’s and MSA which have baffled researchers for years, such as the fact that the clumps of alpha-synuclein end up in different parts of the brain in the two diseases. Another puzzling fact is that MSA is typically more aggressive than Parkinson’s.
‘If a snowball rolls down a hill, at some point it can pick up so much momentum that it just gets bigger and bigger. And it can be pretty serious if you get hit by it, particularly if it collects gravel and stones on its surface along the way.’
A team of scientists at the DANDRITE neuroscience centre at Aarhus University may now have some answers, and four researchers – Professor Poul Henning Jensen, Associate Professor Marina Romero-Ramos, Assistant Professor Nelson Ferreira, and PhD student Hjalte Gram – recently published their hypothesis in an article in the scientific journal Acta Neuropathologica.
The scientific study on which the article is based received funding from the Lundbeck Foundation and the Danish Council for Independent Research as well as the National Institutes of Health (NIH) and the Michael J Fox Foundation for Parkinson’s Research in the USA.
The findings of the four researchers may eventually mean that we will be able to “diagnose Parkinson’s disease and MSA more accurately and give patients more precise and personalised treatment than we can today,” says Professor Jensen.
Snowball effect
We all have in our brains precursors of the “protein clumps” associated with Parkinson’s and MSA – and also Lewy body dementia, another member of the Parkinson’s “family”.
In some cases, these precursor protein clumps take a negative turn and develop into disease – and if the development is fast-moving, the result is a kind of snowball effect. Professor Jensen explains: ‘If a snowball rolls down a hill, at some point it can pick up so much momentum that it just gets bigger and bigger. And it can be pretty serious if you get hit by it, particularly if it collects gravel and stones on its surface along the way.’
This example of the snowball can be used to illustrate the aggressive progression typical of MSA – and the DANDRITE researchers now have an idea of what could be the cause of this aggressiveness.
But there was quite a journey leading up to this point.
“Something that binds”
Around 15 years ago, Professor Jensen was seeking ‘something that could bind to alpha-synuclein aggregates’. In other words, something that would bind to the “protein clumps”.
In order to reveal why these protein clumps in the brain are harmful in diseases such as Parkinson’s and MSA, this knowledge was essential.
At that time, Professor Jensen found what he was looking for.
He identified another protein, p25alfa, that accumulates in the alpha-synuclein clumps found in MSA.
p25alfa plays a prominent role in the study recently published in Acta Neuropathologica.
The four DANDRITE researchers decided to investigate whether this protein was really the cause of the particularly aggressive disease progression characteristic of MSA.
In other words, they sought to discover whether, under certain circumstances, p25alfa – which occurs naturally in the brains of humans and other mammals – can spiral out of control and give the alpha-synuclein protein clumps a “push” hard enough to make them more harmful and induce MSA.
To test this hypothesis, the researchers conducted a range of studies in the laboratory.
They gave a group of mice clumps of alpha-synuclein that had not been in contact with p25alfa.
Another group of mice were given protein clumps that had been exposed to p25alfa.
And the same trial set-up was used for human brain cells, which the researchers tested in a Petri dish.
The results of both the mouse trials and the trials with human cells were striking:
The untreated protein clumps initiated slow pathogenesis – in principle, similar to the rate of development of Parkinson’s disease.
On the other hand, the protein clumps that had been exposed to p25alfa proved to be extremely toxic – and they triggered an aggressive pathological process, identical to the progress of MSA.
‘When we studied the two types of protein clump we’d been working with, we realised they were actually physically different. Their shape was different. They were like keys that open different degrees of toxicity – or snowballs with stones on their surface,’ Professor Jensen explains.
The DANDRITE researchers will now investigate how this new knowledge about the protein clumps can be applied to enable more precise diagnosis of patients with symptoms akin to Parkinson’s.
They will also seek to identify whether the protein clumps of the various patient groups trigger particular disease mechanisms, requiring different treatments.