How faulty proteins in the gut lead to Parkinson’s disease

Parkinson’s disease may have its genesis in the intestine, according to research coming out of the Duke University Medical Centre in North Carolina, US.

In a paper published in the journal JCI Insight, gastroenterologist Rodger Liddle and colleagues suggest that the devastating neurological disease is catalysed by malformed proteins made in the small intestine.

The manufacture of the faulty proteins, however, represents just the first part of a two-step process, the mechanics of which are still being uncovered.

The protein, known as alpha-synuclein, is the focus of a wide range of research by neurologists because it is known to be the primary component of Lewy bodies, the protein clumps that lodge in brain cells and are symptomatic of both Parkinson’s and some types of dementia.

Alpha-synuclein is naturally common in brain cells, and is also found in other parts of the body, including the heart and muscles. Normally not harmful, it becomes toxic and ultimately lethal when something – an as yet unknown agent – causes it to deform, creating a kink its usual spiral structure.

The deformed protein then becomes “sticky”, and starts to clump together, forming Lewy bodies.

The question many researchers are attempting to answer is where the protein misfolding takes place – in the brain, another part of the central nervous system, or elsewhere.

Suspicion that the cause of the problem might lie well away from the brain itself was first raised as early as 2005, when a team led by German anatomist Heiko Braak noted that in some cases of Parkinson’s disease the vagus nerve – which connects the stomach to the brain – and the intestine were involved.

“The disorder might originate outside of the central nervous system, caused by a yet unidentified pathogen that is capable of passing the mucosal barrier of the gastrointestinal tract and … entering the central nervous system,” he and his team wrote.

The idea that somehow Parkinson’s effectively begins in the gut long before symptoms appear has become known as the Braak hypothesis.

There is an increasing amount of evidence that supports the idea, which has already led to some experimental treatments that involve severing the vagus.

Liddle and his colleagues interrogate and potentially confirm the Braak hypothesis by discovering that alpha-synuclein is formed – and sometimes misformed – in endocrine cells in the intestine.

The discovery provides a crucial piece of information that builds on earlier work by Liddle’s team, published in 2015. In that study, the scientists discovered that the gut endocrine cells had a second role – performing, in effect, like nerve cells to communicate with the brain.

This was the first time ever that a non-nerve cell had been observed carrying out nerve cell functions.

The discovery that the endocrine cells also produce alpha-synuclein provides a plausible explanation for how the deformed proteins can spread from the intestine – where there are no proper nerve cells – to the central nervous system.

There is no known cure for Parkinson’s, and management strategies for the disease are markedly unreliable. Liddle says that while his team’s discoveries won’t change this situation in the short-term, they might one day form the basis for a successful intervention.

“Unfortunately, there aren’t great treatments for Parkinson’s disease right now,” he says.

“It’s conceivable down the road that there could be ways to prevent alpha-synuclein misfolding, if you can make the diagnosis early.”