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.
https://www.medscape.com/viewarticle/904217
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).
Abstract
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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