The Journey of alpha-synuclein
Alpha-synuclein got from the intestine to the brain of mice in a month
Polina Loseva, "The Attic"
One of the hypotheses about the origin of Parkinson's disease suggests that pathological proteins, which are considered the engine of neurodegeneration, enter the brain from the digestive system. A new work by American scientists has confirmed that this is possible: within a month after injection into the intestinal wall, proteins reached the brain. The "ladder" for them was the vagus nerve, which transmits signals to the brain about the work of internal organs.
In 2003, researchers who compiled a chronology of the development of Parkinson's disease noticed that the first lesions in the brain occur in the departments associated with the sense of smell and processing signals from the intestine. This allowed them to put forward an infectious theory of the origin of this disease: the pathogen is either inhaled and acts on olfactory receptors in the nose, or swallowed and acts on sensitive cells in the intestinal wall. Through intermediary cells, the pathogen affects neurons, and clusters of alpha-synuclein are formed in them, a protein that destroys nerve tissue and gets lost in Levi's corpuscles - they can be found in the brain of any patient with parkinsonism. Alpha-synuclein spreads like a prion: improperly folded proteins cause healthy proteins to fold and stick together (i.e. converting them into prions), actually causing a protein epidemic in the tissue. Alpha-synuclein spreads further along damaged neurons, from the nose – along the olfactory nerve, from the intestine – along the vagus, eventually reaching the brain and causing the well-known symptoms of Parkinson's disease: first motor disorders, then dementia.
A group of American scientists has set up an experiment confirming the actual possibility of such a scenario. They injected alpha-synuclein filaments (formed from fused proteins) into the muscular membrane of the duodenum, which is densely braided with vagus nerve processes. This is not the first such experiment, but in previous ones alpha-synuclein did not spread through the brain. According to the authors of the article, it was due to low concentrations or an incorrectly chosen injection site – for example, their predecessors injected alpha-synuclein into the colon, where innervation is much worse.
Article by Kim et al. Transneuronal Propagation of Pathological α-Synuclein from the Gut to the Brain Models Parkinson's Disease is published in the journal Neuron.
In this experiment, alpha-synuclein from the duodenum reached the medulla oblongata in a month – the first "station" at the "entrance" to the brain. Three months later, the pest protein arrived in the midbrain and amygdala (the part of the large hemispheres responsible for emotions, among other things), seven months later it reached the hippocampus, olfactory bulb and prefrontal cortex (the anterior part of the frontal lobes). Following this, the mice developed a full range of classic symptoms: motor, cognitive and behavioral.
The amount of dopamine in the striatum of a mouse that was injected with pathological alpha-synuclein (right) and an animal of the control group.
To confirm that a conductor is needed for the alpha-synuclein journey, the researchers cut the vagus nerve parts of the test animals. The connection of the brain with the intestines was really cut off: in conditions of food shortage, the brain did not produce ghrelin, the "hunger hormone", the mice ate worse and gained weight. However, after the introduction of alpha-synuclein, they did not show any symptoms of Parkinson's disease even after seven months of observation.
A similar effect has been observed in humans before: patients who underwent complete or partial dissection of the vagus nerve (to reduce the release of acid in the stomach, for example) were less likely to develop Parkinson's disease than average people.
Nevertheless, the authors of the study urge not to perform such operations on people for preventive purposes. In their opinion, the value of their work lies elsewhere: if the mechanism of transmission of Parkinson's disease from the intestine to the brain is confirmed, then this will give doctors the opportunity to "detect" alpha-synuclein in the early stages of migration and prevent its spread or start therapy on time.
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