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The official blog of Van Andel Institute
31 Oct 2018

Connecting the appendix and Parkinson’s disease

Frequently thought of as a throwaway organ, the appendix may hold the key to better understanding and better treating the second-most common neurodegenerative disease

When most people think of Parkinson’s disease, the appendix likely does not immediately come to mind.

But perhaps it should, according to comprehensive new findings published today in Science Translational Medicine that strongly suggest that the appendix may be a starting point for Parkinson’s, a progressive neurological disorder that affects seven to 10 million people worldwide.

To explain the findings, we caught up with the study’s senior author Dr. Viviane Labrie, an assistant professor at Van Andel Research Institute.

How has our understanding of Parkinson’s disease changed in recent years?

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“Parkinson’s disease for a long time was considered to be a movement disorder involving the destruction of neurons in a specific area of the brain known as the substantia nigra. But it’s now recognized that Parkinson’s disease is a lot more than a motor syndrome; it involves non-motor symptoms as well and many of these non-motor symptoms can arise in people decades before the clinical onset of motor symptoms. So things like trouble sleeping, trouble with smells and GI problems are some of these non-motor symptoms. Specifically, GI problems have been noticed 20 years before the onset of motor symptoms in Parkinson’s disease.

The other thing that we know about Parkinson’s disease is that the hallmark pathology known as Lewy bodies contains this protein called alpha-synuclein and aggregated alpha-synuclein as a component of Lewy bodies can also be seen in the GI tract many years before the onset of motor symptoms in Parkinson’s patients.”

How do changes in the gut impact the brain and possibly contribute to Parkinson’s?

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“We can see these clumps of alpha-synuclein in the GI tract many decades before the clinical onset of motor symptoms. In addition, these clumps of alpha-synuclein don’t like to stay put — they can jump from neuron to neuron and have been known to be able to travel from the GI tract up the nerve that connects the GI tract to the brain and seed and spread, and further cause the spread of these aggregates as well as the destruction of these neurons, eventually leading to Parkinson’s disease.”

Why did you become interested in studying the appendix in Parkinson’s disease? What did you find?

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“We got interested in the appendix because of its role in the immune system in the GI tract; it’s really important for surveilling pathogens and bacteria in the GI, and inflammation and immune responses have a role in Parkinson’s disease.

There’s also evidence in Parkinson’s disease that there’s changes in microbiome the gut bacteria, and the appendix has been shown to be an important regulator of the GI tract microbiome.

In addition to that, there’s evidence that in early Parkinson’s disease cases, there’s aggregated alpha-synuclein — the hallmark of Lewy bodies — that is present in the appendix. So we set out on a full-fledged analysis to know if the appendix could contribute to Parkinson’s disease. We started off by performing two epidemiological analyses. We found that the risk of Parkinson’s disease was decreased by an appendectomy occurring many years prior to Parkinson’s disease. We also saw that in patients the age in which Parkinson’s disease on-set was delayed.

Next, we also saw that in rural individuals the protective effect of an appendectomy was much greater — it was 25 percent reduction in risk for Parkinson’s disease.

What was the most surprising thing that you found?

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“And then we also saw that in the healthy appendix, there was an abundance of aggregated alpha-synuclein and that was really quite a surprise to us, to have so much of this protein that’s associated with Parkinson’s disease to be present in the appendix in healthy individuals, young and old alike, also whether the appendix was inflamed or not inflamed. There was just this huge reservoir of aggregated alpha-synuclein, which suggested to us that the appendix could be important in the initiation of Parkinson’s disease but that the presence of aggregated alpha-synuclein, this feature of pathology, wasn’t just unique to Parkinson’s disease — it was present in everyone.”

If I’m someone who is worried about developing Parkinson’s, should I explore getting my appendix removed?

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“So appendectomy is one of the most common surgeries but all surgeries come with risk. One of the important things to remember is that we saw changes in risk for Parkinson’s disease only if appendectomy occurred two decades before the onset of Parkinson’s disease or even longer, so only early appendectomies were protective. But even still, removing the appendix may change how your immune system works and your microbiome works. And so you may show changes in risk for Parkinson’s disease but you might also change the risk for other diseases that we don’t fully understand yet, so we’re really just starting to understand the role of the appendix in Parkinson’s disease.”

How else could your findings possibly impact treatments for Parkinson’s?

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“Managing instead the inflammation that occurs in individuals that are prone to develop Parkinson’s as well as the protein that is a hallmark of Parkinson’s in the appendix might be a much better therapeutic solution. If we manage inflammation or this protein that is characteristic of Parkinson’s disease, we might not only hit the appendix but the entire GI tract all at once. And so, in this way, we have a much more effective therapeutic effect.”

What do your findings NOT say?

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“What we’re not trying to stay in our study is that just because you have an appendix, that causes Parkinson’s disease. We’re also not saying that everyone should have their appendix removed, or that all cases of Parkinson’s start in the appendix.

What we are saying is that the appendix has an abundance of this protein that is associated with Parkinson’s disease, but location is everything — location, location, location. So, this aggregated protein in the appendix is a very normal thing. It’s present in all individuals — healthy, young and old, inflamed and non-inflamed — everybody. But if this protein were to leave the appendix and go to the brain that could be a trigger for Parkinson’s disease, so the location of this protein is really essential.

Also, what our study does tell us is that the presence of this clumped protein is not what defines a Parkinson’s patient, it’s actually other mechanisms that determine its ability to move from cell to cell or eventually move to the brain. So, in our future studies, we’re trying to understand those mechanisms that determine why does the protein in some very rare instances decide to leave the GI tract and go to the brain and cause Parkinson’s disease.”

What is the most exciting thing happening right now in Parkinson’s disease research?

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“What I’m most excited about in Parkinson’s research is it’s expanding from just a purely dopamine and brain disorder to something that involved much more — peripheral systems, immunology, the GI tract. And what gets me really interested is that now we’re opening the door to a whole a new line of therapies, therapies that don’t just target the destruction of neurons in the brain but also that target the mechanisms that may be occurring in places outside of the brain like the GI tract, like the appendix.”

The appendix: Fighting an undeserved reputation

Many people think of the appendix as a throwaway organ, one with no real role in the body. But that couldn’t be further from the truth.

In reality, the appendix is an important part of immune system regulation in the gut. It plays a critical role in monitoring pathogens and even acts as a backup hard drive that can repopulate the entire microbial environment of the intestine should it be lost due to injury or illness.”