Friday, November 2, 2018

The appendix and Parkinson's disease

Two new epidemiologic studies have suggested an important role for the appendix in the origin of Parkinson's disease.

One large study, which involved the whole population of Sweden and had a 50-year follow-up, found that individuals whose appendix had been removed in early life had a 20% lower risk of developing Parkinson's disease later in life.

The second study, from the United States, found that for Parkinson's disease patients whose appendix had been removed earlier in life, the age at disease onset was later than for those who had not undergone an appendectomy.

Both studies were published online October 31 in one article in Science Translational Medicine.
The researchers also found a high level of alpha-synuclein clumps in appendix tissue both from patients with Parkinson's and healthy individuals. Alpha-synuclein is known to be a factor in the pathology of Parkinson's disease in the brain.

"We are not advocating removing the appendix as a preventative treatment for Parkinson's, and we are not saying that if you have had an appendectomy, you will not get Parkinson's," Labrie said. "But what we can say is that the appendix is a potential reservoir for the clumped form of alpha-synuclein that is associated with Parkinson's disease in the brain. While this clumped alpha-synuclein appears to be normal in the appendix, it is pathogenic in the brain, so location is everything.

"These alpha-synuclein clumps are present in the appendix in almost everyone, but we think that in Parkinson's patients, these clumps escape via the vagal nerve to the brain," she said. Alternatively, inflammation of the gastrointestinal (GI) tract that involves the appendix may play a role, she added.

"Our findings suggest that the appendix is one possible initiation site for Parkinson's disease. But removing the appendix does not completely eliminate the disease, so it likely that there are other key sites of origin too," Labrie said. "Rather than advocating universal appendectomy, it would therefore be better to try and control the excessive formation of alpha-synuclein clumps in the GI tract altogether and also to try and prevent their escape from the GI tract to the brain."…

Labrie explained that Parkinson's disease has been regarded as a movement disorder driven by loss of dopaminergic neurons in the substantia nigra region of the brain. However, in the past decade, it has become evident that the disease is not just a motor disorder but also encompasses a whole range of nonmotor symptoms, including GI symptoms that often occur years or even decades before the motor symptoms develop.

Results showed that the risk of developing Parkinson's disease was reduced by almost 20% among people who had had their appendix removed.

The incidence of Parkinson's disease was 1.60 per 100,000 person-years among individuals who had undergone an appendectomy, compared to 1.98 for control persons, representing a risk reduction of 19.3% (95% confidence interval, 10.4% - 27.2%).

The risk reduction was even greater (around 25%) in people who lived in rural areas, indicating that environmental factors may also be involved.

In the Swedish study, among those who developed Parkinson's disease, the age of diagnosis was on average 1.6 years later in individuals who had undergone an appendectomy 20 or more years earlier than in persons who had not undergone an appendectomy.

From the second dataset — the US Parkinson's Progression Markers Initiative — the researchers analyzed data on 849 patients with Parkinson's disease and found that 6.5% had undergone an appendectomy earlier in life.

In those who had undergone an appendectomy, the age of onset of Parkinson's disease was on average 3.6 years later than in those patients who had not had their appendix removed.

The researchers examined appendix samples from 48 healthy individuals and found a "remarkable abundance" of the clumped form of alpha-synuclein in 46 of 48 samples.

"This is important, as previously, we thought these clumps of alpha-synuclein would occur only in Parkinson's patients. But our results show that in the appendix, they are equally abundant in healthy individuals," said coauthor Patrik Brundin, PhD. "Levels were also similar in normal and acutely and chronically inflamed appendix tissue and in younger and older people.

"It seems like the presence of alpha-synuclein aggregates in the nerve cells of the appendix is not a feature unique to Parkinson's disease, as it is found in almost all individuals. It is also not associated with ageing," Brundin added. 

However, with further biochemical analysis, the researchers found that certain forms of alpha-synuclein were more common in the appendix of Parkinson's patients. In particular, there was a 4.5-fold increase of truncated alpha-synuclein, which is prone to extremely rapid clumping, the lead author of the article, Bryan Killinger, PhD, said.

"Our data suggest that there is a unique shortening of alpha-synuclein in the appendix, which accelerates its ability to form clumps and is a risk factor for Parkinson's disease," he stated. "Future research could focus on this truncated form of the protein."

Commenting on the study, Orla Smith, PhD, editor of Science Translational Medicine, said: "This paper presents clear evidence that pathogenic events take place in the GI tract and enteric nervous system.

"The authors show that the human appendix may be a reservoir for pathogenic forms of alpha-synuclein that are known to cause Parkinson's disease when mutated in the brain," she said.

Killinger BA, Madaj Z, Sikora JW, Rey N, Haas AJ, Vepa Y, Lindqvist D, Chen H, Thomas PM, Brundin P, Brundin L, Labrie V. The vermiform appendix impacts the risk of developing Parkinson's disease. Sci Transl Med. 2018 Oct 31;10(465).

The pathogenesis of Parkinson's disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology-associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.

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