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26 June 2019 - The Guardian - Growing evidence suggests Parkinson's disease starts in gut

Nicola Davis

gut-brain axis

Research shows key proteins in disease can spread from gastrointestinal tract to brain

Evidence that Parkinson’s disease may start off in the gut is mounting, according to new research showing proteins thought to play a key role in the disease can spread from the gastrointestinal tract to the brain.

The human body naturally forms a protein called alpha-synuclein which is found, among other places, in the brain in the endings of nerve cells. However, misfolded forms of this protein that clump together are linked to damage to nerve cells, a deterioration of the dopamine system and the development of problems with movement and speech – hallmarks of Parkinson’s disease.

The latest findings, which are based on studies in mice, back up a long-held theory that abnormally folded alpha-synuclein may start off in the gut and then spread to the brain via the vagus nerve – a bundle of fibres that starts in the brainstem and transports signals to and from many of the body’s organs, including the gut.

“It supports and really provides the first experimental evidence that Parkinson’s disease can start in the gut and go up the vagus nerve,” said Ted Dawson, professor of neurology at the Johns Hopkins University school of medicine and co-author of the research.

The researchers say the way the misfolded alpha-synuclein spreads in the brains of the mice, and the animals’ symptoms, closely mirrors the disease in humans.

“We have what we think is a really accurate [animal] model that can be used to work out mechanisms – but also to test therapies,” said Dawson, saying one possibility may be to interfere with the misfolding of alpha-synuclein in the gut to stop Parkinson’s disease in its tracks.

The study comes months after a different group of researchers revealed that people whose appendix was removed early in life had a reduced risk of later developing Parkinson’s disease – a finding experts said also supports the idea the disease may begin in the gut.

Writing in the journal Neuron, Dawson and colleagues describe how they conducted a series of experiments involving more than 100 mice.

First, the team injected abnormally folded alpha-synuclein into the gut of healthy mice and tracked where the protein turned up.

After one month the misfolded protein was present in several structures within the brainstem, while at three months it was also found in other regions of the brain including the amygdala and part of the midbrain rich in dopamine neurons. After seven months it was present in even more areas.

The team say that fits with the way markers of Parkinson’s disease are distributed throughout the human brain at different stages in the disease.

Further work revealed the mice showed a drop in dopamine levels in the brain, followed by a progressive loss of dopamine neurons from seven months. They also showed problems in their motor skills – such as having difficulties in building a nest – as well as memory, anxiety and behaviour problems.

The team repeated the injection of misfolded alpha-synuclein both in mice with a severed vagus nerve as well as mice genetically engineered to be unable to produce normal alpha-synuclein. Neither type of mice ended up with the misfolded protein in the brain, damage to their dopamine system or any motor, memory or behavioural problems .

The team say these results suggest misfolded alpha-synuclein travels to the brain via the vagus nerve, with the injected proteins triggering normal alpha-synuclein in the mice to become misfolded, resulting in a sort of domino effect that leads to misfolded proteins reaching the brain.

However there are some curiosities. For example, while problems with smell is an early symptom of Parkinson’s disease in humans, the olfactory system was not affected in mice until several months after injection of the misfolded alpha-synuclein into their gut.

And mysteries remain, including why some people have clumps of the abnormal protein in the brain but no symptoms of Parkinson’s disease – and how alpha-synuclein becomes misfolded in the first place.

Dr Beckie Port, research manager at the charity Parkinson’s UK, said the latest research builds on previous studies.“This study adds support to a growing base of evidence [implying] that changes in the gut play a key role in the initiation of Parkinson’s, although it is not believed to be the only place where the condition may start,” she said.

“By identifying and halting these changes before they reach the brain, we may be able to prevent the majority of Parkinson’s symptoms ever appearing and improve the lives of people who will be affected.”