Parkinson’s symptoms invade from the gut

A cohort of lab rats, which were genetically manipulated and programmed to produce extremely large amounts of the protein alpha-synuclein, are the main protagonists in a research article on Parkinson’s disease.

The article was published in Acta Neuropathologica, one of the world’s leading neuroscience journals, and its authors are a team of Danish, German and Austrian scientists headed by Professor Per Borghammer from the Department of Nuclear Medicine and PET at Aarhus University Hospital.

The researchers used genetically manipulated rats to verify a hypothesis, put forward in 2003 by German neuropathologist Heiko Braak, that in a good many cases Parkinson’s disease begins in the patient’s gut.

Parkinson’s disease has been known to medical science for around 200 years and, ultimately, the disease causes the patient’s brain to break down due to an accumulation of alpha-synuclein, which destroys the nerve cells. If the disease begins in the patient’s gut, it has to spread to the brain in some way or other, and this is at the heart of Braak’s hypothesis:

It predicts that clumps of alpha-synuclein, which have formed in the gut’s nervous system, travel backwards to the brain via the vagus nerve – a major nerve which begins in humans and other mammals in the brain stem and spreads out into the body where it controls bowel function, among other things.

The Aarhus researchers have been testing aspects of Braak’s hypothesis for some years. Professor Per Borghammer, who is funded by the Lundbeck Foundation, explains:

‘In the study on which the Acta Neuropathologica article is based, clumps of alpha-synuclein were injected into the small intestines of the rats. The rats had already been genetically programmed to produce abnormally large amounts of this protein themselves – so this gave them a Parkinson’s profile. We then needed to see whether this bombardment with alpha-synuclein could produce Parkinson’s pathology in the animals’ brains. This was the idea behind our trials.’

Rapid development

The study was conducted in Aarhus. Nathalie Van Den Berge, a postdoc in Per Borghammer’s team and first author of the scientific article, performed the injections – and after two months, the first findings could be assessed.

‘At that stage, we could already see that the alpha-synuclein had travelled up to the animals’ brains and it had caused immense damage in the precise regions that are affected when humans suffer from Parkinson’s disease. And when we checked again, four months after the injections, the damage was even more widespread. It was remarkable how rapid the development was,’ says Per Borghammer.

Can also reach the heart

By the time doctors diagnose Parkinson’s disease, the patient’s heart has already been deprived of a significant proportion of its nervous system.

For this reason, Nathalie Van Den Berge and Per Borghammer wanted to investigate whether this type of nerve damage in the heart could also be provoked by injecting alpha-synuclein into the bowels of the rats: Can the harmful protein travel from the gut to the heart via nerve pathways?

‘The answer is yes, and we were the first to demonstrate this in animal trials. It’s an important finding because we’ve never really understood why the heart’s nervous system gets damaged so early and to such a degree in many Parkinson’s patients,’ says Per Borghammer.

But what can we conclude from these trials in relation to Parkinson’s disease in humans?

In short, in Professor Borghammer’s opinion, it significantly reinforces the suspicion that it is likely that many cases of Parkinson’s disease begin in the patient’s gut:

‘It offers no universal explanation but it’s a valuable contribution to our understanding of the complex issues underlying Parkinson’s disease. And it’s also a valuable find for those in the research environment attempting to develop drugs to treat the disease.’