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Two new epidemiological studies have suggested an important role of the appendix in the origin of Parkinson's disease.
A large study, which covered the entire Swedish population and was being followed up after 50 years, revealed that individuals whose appendix had been removed early in life risked 20% less to develop Parkinson's disease later in life.
The second study, conducted in the United States, found that in patients with Parkinson's disease whose appendix had been removed earlier in life, age at onset of the disease was later only for those who had not undergone an appendectomy.
Both studies were published online on October 31 in an article by Translational medicine science.
"Overall, our research shows that the appendix is a tissue site that plays a key role in the onset of Parkinson's disease and is attracting increasing interest in the potential of gastrointestinal therapies for the treatment and management of Parkinson's disease. prevention of Parkinson's disease ", Viviane, lead author. Labrie, PhD, Van Andel Research Institute, Grand Rapids, Michigan, said.
Labrie was speaking at a press conference organized by the American Association for the Advancement of Science, publisher of Translational medicine science. The press conference brought together several article authors, all from the Van Andel Research Institute.
The researchers also found a high rate of agglutination of alpha-synuclein in appendiceal tissue from patients with Parkinson's disease and healthy individuals. Alpha-synuclein is known to play a role in the pathology of Parkinson's disease in the brain.
"We are not advocating removal of the appendix as a preventative treatment for Parkinson's disease, and we are not saying that if you have had an appendectomy, you will not get Parkinson's disease," Labrie said. . "But what we can say is that the appendix is a potential reservoir for the clustered form of alpha-synuclein associated with Parkinson's disease in the brain.This clustered alpha-synuclein appears to be normal in the appendix it is pathogenic in the brain, so the location is everything.
"These clusters of alpha-synuclein are present in the appendix in almost everyone, but we believe that in patients with Parkinson's disease, these clusters escape via the vagal nerve. to the brain, "she said. Alternatively, inflammation of the gastrointestinal tract (GI) that involves the appendix can play a role, she added.
"Our findings suggest that the appendix is a possible initiation site for Parkinson's disease, but removing the appendix does not completely eliminate the disease, so it is likely that there are also other key origin sites, "Labrie said. "Rather than advocating universal appendectomy, it would therefore be best to try to completely control the excessive formation of alpha-synuclein aggregates in the gastrointestinal tract and prevent their escape." from the brain to the brain. "
Non-motor symptoms
Labrie explained that Parkinson's disease was considered a movement disorder caused by the loss of dopaminergic neurons in the region of the brain's dark substance. However, over the past decade, it has become clear that the disease was not just a motor disorder, but also encompassed a range of non-motor symptoms, including gastrointestinal symptoms that often manifested as symptoms. years, even decades, even before the onset of motor symptoms.
"More clinical attention is now being paid to the gastrointestinal tract, not only in terms of symptoms, but also as a potential site for the development of Parkinson's disease," she added.
The typical pathology of Parkinson's disease is the appearance of Lewy bodies – tufts of alpha-synuclein – in the brain. There is evidence that in patients with Parkinson's disease, clusters of alpha-synuclein are also present in the gastrointestinal tract, sometimes many years before the onset of motor symptoms, has noted Labrie.
"In addition, it seems that alpha-synuclein does not like to stay in place," she said. "It can move from neuron to neuron and back up nerves connecting the intestine to the brain, where it causes neurotoxic effects." One of the first brain areas in which these masses of alpha-synuclein are observed in patients with Parkinson's is the vagal nerve terminal, which connects the gut to the brain, and the disease progresses and progresses from there. "
Labrie said that she and her colleagues wanted to study specific areas of the intestine that might be involved in Parkinson's disease and centered on the appendix, because the appendix plays an immunomodulatory role in the body.
"He is responsible for sampling and modulating pathogens and stimulating the immune response," she said. "In addition, the intestinal microbiome has been linked to Parkinson's disease and the appendix is a storage area for intestinal bacteria and may affect the regulation of bacteria in the gastrointestinal tract." So we conducted the current studies on the effects of the removal of the Schedule on Risk of Parkinson's Disease. "
20% risk reduction
The researchers first analyzed data from the Swedish National Patient Registry, which documented hospitalizations and surgeries for the entire Swedish population.
They identified all Swedish subjects whose appendix had been removed since 1964. Each of these patients was paired with two control subjects from the general population who did not undergo appendectomy. Researchers analyzed data from a total of 1.7 million people. Follow-up data were available for a period of up to 52 years.
The results showed that the risk of developing Parkinson's disease was reduced by almost 20% among people whose appendix had been removed.
The incidence of Parkinson's disease was 1.60 per 100,000 person-years in appendicectomy patients, compared to 1.98 for control subjects, representing a 19.3% reduction in risk. (95% confidence interval, 10.4% to 27.2%).
Risk reduction was even greater (around 25%) among people living 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 subjects with appendicectomy 20 years or older earlier than in those not having undergone an appendix.
Delay in the onset of the disease
Researchers analyzed data from 849 patients with Parkinson's disease in the second set of data – the Parkinson's Progress Markers Initiative (US) – and found that 6.5% had an appendectomy earlier in life.
In patients who had an appendectomy, the onset of Parkinson's disease was on average 3.6 years later than in patients whose appendix had not been removed. .
The researchers examined appendix samples from 48 healthy individuals and found a "remarkable abundance" of the clustered form of alpha-synuclein in 46 out of 48 samples.
"This is important because we previously thought that these clusters of alpha-synuclein would only occur in patients with Parkinson's disease.But our results show that in the appendix they are also abundant in individuals in good health, "said co-author Patrik Brundin. "Levels were also similar in normal and severely affected appendicular tissues and in younger and older people.
"It appears that the presence of aggregates of alpha-synuclein in the nerve cells of the appendix is not a characteristic feature of Parkinson's disease because it is found in almost all individuals. It's also not associated with aging, "Brundin added.
Truncated form of alpha-synuclein
However, with further biochemical analysis, the researchers found that some forms of alpha-synuclein were more common in patients with Parkinson's disease. In particular, there has been a 4.5-fold increase in truncated alpha-synuclein, which is prone to an extremely fast agglutination, said senior author Bryan Killinger. , PhD.
"Our data suggest that there is a unique shortening of alpha-synuclein in the appendix, which accelerates its ability to form clumps and constitutes a risk factor for Parkinson's disease," he says. did he declare. "Future research could focus on this truncated form of the protein."
Commenting on the study, Orla Smith, PhD, editor-in-chief of Translational medicine science, said: "This document presents clear evidence that pathogenic events occur in the gastrointestinal tract and the enteric nervous system.
"The authors show that the human appendix can be a reservoir for the pathogenic forms of alpha-synuclein known to cause Parkinson's disease when they are mutated in the brain," she said. declared.
"Translational medicine science is excited to publish this carefully conducted study, which broadens our understanding of the early stages of one of the most common and debilitating neurological diseases. "
Sci Transl Med. Posted online October 31st. Full text
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