Bacteria in the human gut can produce proteins that look remarkably similar to those involved in diseases such as Parkinson’s and Alzheimer’s, according to analyses by scientists from the Wrocław University of Science and Technology.
Neurodegenerative diseases such as Parkinson’s and Alzheimer’s are associated with the accumulation of amyloid fibril deposits in the brain, which damage nerve cells and impede neuronal function.
In Parkinson’s disease, fibrils made of the protein alpha-synuclein accumulate in the brain, while in Huntington’s disease, it is huntingtin. In Alzheimer’s disease, deposits of the beta-amyloid 1-42 peptide and tau protein tangles form, says Professor Małgorzata Kotulska from the Wrocław University of Science and Technology.
Amyloidogenic proteins often have a dual nature. If folded properly, “according to the recipe”, they readily dissolve in water and perform their normal functions in the body.
The problem arises when the same sequence of amino acids unfolds and folds according to a different pattern. Instead of a useful tool, it becomes a harmful, insoluble filament that can gradually disrupt the connections between neurons in the brain.
Neurodegenerative diseases therefore result from “good” molecules taking a “wrong” shape.
What causes a properly folded molecule to lose its proper shape? Researchers point to the potentially contagious nature of this phenomenon. Sometimes, when a properly folded molecule comes into contact with a misfolded one, it takes on the incorrect amyloid filament structure, passing it on like a domino effect.
This mechanism is known, for example, from prions, which are responsible for mad cow disease.
Kotulska and her colleagues became interested in so-called functional amyloids. Amyloid proteins folded into fibres can also be produced intentionally by various organisms, with the fibre structure serving a useful purpose.
In humans, one example is the PMEL protein, which provides a scaffolding for pigment in the skin. Bacteria, however, make particular use of such structures. They create biofilms from amyloids – extremely resistant protective membranes associated with things such as plaque on teeth or the slippery layer in sink drains.
“This intrigued us in the context of the bacteria inhabiting our intestines. We asked ourselves: Does the increased presence of bacterial amyloid proteins in the body have anything to do with neurodegenerative diseases? Do bacterial proteins interact with our own proteins and influence our risk of developing the disease?” Kotulska says.
In a paper published in Npj Biofilms and Microbiomes, researchers from Wrocław, working with scientists from Kraków and Göttingen, analysed extensive data previously collected during studies of the gut microbiomes of patients with Alzheimer’s disease, Parkinson’s disease and a control group.
By sifting through sequenced bacterial genomes, algorithms under the supervision of the scientists searched for genes capable of producing amyloid proteins or closely related ones, and then screened them for their potential to form fibrils. This meticulous digital work required enormous computing power.
In the microbiomes of Parkinson’s disease patients, the researchers found an increased presence of bacteria producing amyloid proteins.
In particular, they identified several specific groups of these proteins that could interact with the human alpha-synuclein protein, characteristic of the condition.
A generally high number of proteins with amyloid potential was also observed in people with Alzheimer’s disease, although the influence of specific families could not be identified.
The results from the control group – which did not demonstrate an increased presence of any specific amyloid group or an increase in their overall abundance – provided a comparison for the other findings.
This research sheds light on one possible scenario for the development of Parkinson’s disease. The scenario assumes an indirect involvement of gut bacterial proteins in the disease process.
For example, when a leaky gut occurs, bacterial amyloids come into contact with the human protein alpha-synuclein, which occurs naturally in the intestinal nervous system. This proximity provokes human alpha-synuclein to change its shape into a filament, to which it has a natural, albeit undesirable, tendency.
The misfolded protein begins to transfer its new structure to other molecules, a process that travels along the vagus nerve – like a communication cable – from the abdomen to the brain.
“As part of our previous work, we built open-source bioinformatics tools, available online, that allow us to predict whether two given amyloid proteins will interact and form a common fibre. Now, in our latest paper, we have shown that the microbiomes of Parkinson's disease patients contain significantly more bacteria producing specific amyloid proteins that can interact with human proteins prone to forming fibre structures”, Kotulska comments.
Why the presence of bacterial amyloid proteins leads to neurodegenerative diseases in some people, while others are able to defend themselves against their effects, remains a mystery.
“The microbiome is a kind of drug and metabolite factory that we carry within us. However, to safely control it, we must first thoroughly understand the relationships between specific bacterial proteins and our health. And then the door will open to a future in which we will be able to deliberately regulate the composition of our gut microbiome for preventive or therapeutic purposes”, the researcher concludes.
Ludwika Tomala (PAP)
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