[ad_1]
TheIn layers of the human appendix, deposits of alpha-synuclein, a protein prone to gelation, look like sticky rice. Recognized primarily for their agglutination in the brains of people with Parkinson's disease, the aggregates of alpha-synuclein found in the appendages of healthy people made the headlines a few weeks ago.
Is the appendix not useless enough, even dangerous when it is inflamed? Is it also a gateway to brain disease?
In fact, a link between Parkinson's protein and the appendix has been known for a few years. Now, new experiences reported in Translational medicine science confirm the connection and suggest a protective role for the appendectomy. But instead of advising people to get rid of their appendages, researchers believe that their discoveries pave the way for a new target for drug discovery for Parkinson's disease.
"We have shown that the appendix is a hub for the accumulation of clustered forms of alpha-synuclein proteins, implicated in Parkinson's disease. This knowledge will be valuable in exploring new prevention and treatment strategies, "said Bryan Killinger, lead author of the report and a postdoctoral fellow at Viviane Labrie's laboratory at the Center for Neurodegenerative Science at the Van Andel Research Institute in Grand Rapids. .
The much-maligned annex is very active. It produces 71% of all 20,000 types of human proteins, so it must act. The 200 most abundant proteins are also very present in the spleen, tonsils and lymph nodes, creating a quartet of body parts that protect us from infections. In addition, the tiny organ regulates the microbiomes of the small intestine and the large intestine, serving as a reserve to replenish resident bacteria.
Shape changers
Alpha-synuclein is one of many proteins that naturally bend in addition to a three-dimensional form, depending on the chemical attractions and repulsions between their parts. (Imagine how a sprig of cooked spaghetti could land in different ways.) Although a single gene tells a cell how to synthesize a single molecule of a protein – a monomer – rare alternative forms can trigger a character sticky which agglomerates the monomers into deposits.
The brain is particularly vulnerable to diseases related to protein aggregation. The misfolded TDP-43 protein is at the origin of a familial form of ALS, as is the beta amyloid precursor protein and tau proteins for some forms of familial Alzheimer's disease.
Parkinson's has a different protein. "Alpha-synuclein is normally present in body tissues in a native state called" disordered monomer ". When alpha-synuclein aggregates into an aggregate, it is associated with the pathology characteristic of Parkinson's disease, Lewy's disease. neurotoxic effects in the brain, "said Viviane Labrie at Genetic literacy project.
The harmless form of alpha-synuclein was present in many organs, including the brain and the appendix. "In our study, we found that Associate The forms of alpha-synuclein, the grouped form relevant to Parkinson's disease, were abundant in the human appendix. If the aggregated alpha-synuclein protein leaves the gastrointestinal tract, as indicated in the appendix, goes to the brain, we think it could trigger Parkinson's disease, "said Dr. Labrie.
Links to the annex
Alpha-synuclein inhabits a different neighborhood of the pocket-shaped organ than abundant lymphoid tissue. It accumulates inside the neurons that are part of the gill network that innervates the gastrointestinal tract (GI), called enteric plexus. From there, the vagus nerve sends its axons to the brainstem.
Could alpha-synuclein sometimes cling to the vagus nerve at the brainstem, and from there to substantia nigra, the epicenter of Parkinson's? An origin in the appendix might explain why gastrointestinal symptoms, especially constipation, can manifest up to 20 years before Parkinson's motor symptoms.
In 2007, a trio of researchers from the Essex Neuroscience Center (UK) proposed a scenario linking the gastrointestinal tract to the brain: swallowing viruses and bacteria in the nasal mucosa, which travels along the enteric nerves of the Stomach to the brain. But Parkinson's is not an infection.
A 2014 study found that ungrouped alpha-synuclein was found in the mucosa of appendages in healthy people. University of Ottawa researchers hypothesized that an appendectomy could affect Parkinson's risk.
In 2015, Danish researchers added another piece to the puzzle. They found a lower incidence of Parkinson's disease in people who had had vague cut nerves to treat ulcers.
Other studies have shown that alpha-synuclein forms deposits in the gastrointestinal tract years before the onset of Parkinson's motor symptoms. The delay is critical because young people tend to have appendicectomies, while the older ones develop Parkinson's disease. That's why it's important for a study to cover decades of data. Several researchers may not have identified an appendectomy-Parkinson link because they only dated back a few years, the researchers write.
Biochemistry meets epidemiology
The new job examined two databases. The Swedish National Register of Patients has followed all Swedes diagnosed since 1964, thus meeting the criterion of time. Of 1,698,000 individuals, 551,647 had appendectomy and 2,252 of them developed Parkinson's disease. This is a 19.3% lower risk than those who developed the disease but have retained their appendages. And the age at diagnosis was, on average, 1.6 years later in people who had had an appendectomy.
A second database, the Parkinson's Progress Markers Initiative, covered people with the disorder and included the age at which symptoms began, demographic factors and genetic information (most cases of Parkinson's are not diagnosed with Parkinson's disease). hereditary). Of the 849 cases, 54 had an appendectomy.
Having an appendectomy 30 years or more before the onset of the first symptoms of Parkinson's disease was associated with an average delay of 3.6 years. However, no delay was observed in people with Parkinson's disease, suggesting that the application of an appendectomy could only have a protective effect in cases of exposure to environmental risk factors, such as pesticides used in agriculture.
The severity of Parkinson's disease was similar whether a person had an appendectomy or not. This suggests that the influence of the appendix is to germinate the neurological disease and not accelerate it, the researchers wrote.
The researchers also probed the appendages of 48 healthy people (other than their appendicitis) of varying ages and were surprised to find that 46 of them had a large amount of gummy form. alpha-synuclein believed to be associated only with Parkinson's disease. The protein was scattered in neurons and in some macrophages, the scavenging cells of the immune system.
Yet another series of experiments captures the appendix in action, in vitro. Researchers have prepared a kind of soup composed of healthy appendages and alpha-synuclein monomers made using recombinant DNA technology, that is, to say outside the body. Indeed, the appendix soup made the monomers sticky, as in the Parkinson's brain.
"We were surprised to see that the pathogenic forms of alpha-synuclein were so ubiquitous in the appendages of people with and without Parkinson's disease. It seems that these aggregates – although toxic when they are in the brain – are quite normal when they are in the appendix. This clearly suggests that their mere presence can not be the cause of the disease, "said Dr. Labrie. Something more, perhaps a confluence of events, allows the appendix to increase the risk of Parkinson's, which affects less than 1% of the population, she added. "That's what we plan to look at next: what factor or what factors tip the balance in favor of Parkinson's disease?"
Will "prophylactic appendectomy" become a thing? Unlikely, as the protection offered by appendix removal is not huge. Researchers put it this way in their paper: "Overall, PD was diagnosed in 1.17 out of every 1,000 people who had an appendectomy, compared to 1.4 per 1,000 in the general population."
While young people are unlikely to volunteer to protect themselves against a neurological disease that probably will not manifest for decades, the link between the malignant digestive organ and the Parkinson's brain offers a new and attractive drug target.
"Our results indicate that the appendix is a site of origin for Parkinson's disease and paves the way for the development of new treatment strategies that exploit the role of the gastrointestinal tract in the development of the disease." Said Dr. Labrie.
Ricki Lewis is the lead contributor of GLP and focuses on gene therapy and genetic modification. Holder of a doctorate in genetics, she is a genetic consultant, scientific writer and author of The Forever Fix: Gene Therapy and The Boy Who Saved It, the only popular book on gene therapy. ORGANIC. Follow her on her website or on Twitter @rickilewis
[ad_2]
Source link
