Scientists talked about a new approach to the fight against Parkinson's disease
Scientists are exploring a new approach to slow down Parkinson's disease. They intend to limit the entry of pathological forms of alpha-synuclein protein into nerve cells and at the same time enhance its excretion from the brain. In experiments on mice, interfering with one of the protein capture mechanisms has already helped protect neurons. How this process works and what else the researchers have yet to check is in the Izvestia material.
Why alpha-synuclein becomes dangerous
Alpha-synuclein is also present in the healthy brain, where it participates in the transmission of signals between nerve cells. The problem occurs when the protein acquires an irregular spatial structure. Such molecules can combine into pathological clusters inside neurons.
Alpha-synuclein is a part of Levy bodies, intracellular inclusions characteristic of Parkinson's disease and some forms of dementia. However, scientists are also attracted to processes outside the cell: pathological forms of protein can exit one neuron and enter another.
"As soon as it begins to accumulate in one neuron and cause disease, it can leave the first cell and enter the second. This is how it spreads through the brain," explained Stephen Strittmatter, professor of neurology.
Therefore, scientists want to find out what happens to alpha-synuclein in the gap between cells. Will it be removed from the brain or will it be captured by the next neuron? According to the researchers, the further spread of the pathological process may depend on this ratio.
The project was supported by the Aligning Science Across Parkinson's (ASAP) program. It brings together three teams that study protein uptake by neurons, its removal through the lymphatic drainage system, and new ways to model the disease.
How does a pathological protein get into neurons
Strittmatter's group began by searching for proteins on the surface of nerve cells capable of binding the pathological alpha-synuclein. The researchers tested several thousand candidates and found only a small group of suitable molecules.
Two proteins, the metabotropic glutamate receptor of the fourth type, or mGluR4, and NPDC1, attracted special attention. They are present in dopamine neurons, which are particularly vulnerable in Parkinson's disease.
In the study, the scientists showed that mGluR4 and NPDC1 form a complex involved in the binding and uptake of alpha-synuclein fibrils, elongated protein aggregates. After the introduction of such fibrils into the brains of ordinary mice, loss of dopamine neurons was observed. In animals with the disabled gene of one of the two proteins, these cells were protected.
In the culture of neurons, the absence of both proteins also prevented the binding of fibrils, the accumulation of pathological alpha-synuclein, and the loss of synapses, the contacts through which cells transmit signals.
These results indicate a possible target for therapy. If it is possible to interfere with the work of the complex, scientists expect to limit the flow of pathological protein into new cells. So far, the protective effect has been shown in experimental models.
Why does disabling a gene not mean the appearance of a drug?
Of particular interest to researchers is mGluR4. However, there are several unresolved issues between the genetic experiment and the use of the drug. Disabling the gene allows us to test the role of the protein in the development of pathology, but in itself does not show whether it will be possible to achieve the same result with the help of a drug.
"So far, we have only completely disabled the gene. But the introduction of a drug that affects the mGluR4 protein at different points in time would allow us to learn much more about its potential as a therapeutic target and at what stage of the disease it plays a role," said Strittmatter.
Scientists will have to figure out which intervention will be effective and when it should be carried out. Protecting cells before exposure to a pathological protein and trying to stop an already developing process can give different results.
The search for suitable compounds is being conducted jointly with researchers from Columbia University and Vanderbilt University. The latter's team already has experience in developing substances that act on metabotropic glutamate receptors. Now the project participants want to test their capabilities in the context of alpha-synuclein pathology.
How to speed up protein elimination from the brain
The second part of the project is devoted to the removal of pathological alpha-synuclein from the extracellular environment. The group of ophthalmology and immunobiology specialist Eric Song is engaged in this area.
The lymphatic system is involved in the removal of metabolic products and other substances from tissues. Song's team intends to study how the lymphatic drainage system connected to the brain removes alpha-synuclein and whether this process can be enhanced.
Both directions should complement each other. Limiting protein uptake by neurons is designed to reduce its entry into cells, and accelerated elimination is designed to reduce the amount of pathological alpha—synuclein remaining between them. The researchers suggest that a combination of these interventions may help slow the spread of the disease.
Song had previously studied the possibilities of influencing the lymphatic system in eye diseases. According to him, similar approaches have also shown encouraging results in Alzheimer's disease research. Now scientists want to test whether this mechanism is applicable to Parkinson's disease.
At the same time, the effectiveness of enhanced lymphatic elimination of alpha-synuclein in patients has yet to be established. In the project description, this approach is presented as a research area.
Why do scientists need a new model of Parkinson's disease
To test future interventions, we need a model that allows us to study the pathological protein specifically in the extracellular environment. Common methods of reproducing individual signs of Parkinson's disease in mice do not fully meet this task.
Usually, animals are injected with prepared alpha-synuclein fibrils or their genes are altered so that the body produces an increased amount of protein. Such experiments help to investigate specific mechanisms, but do not reproduce the entire composition of the environment in which the disease develops in humans.
The group of neurology and neuroscience specialist Le Zhang proposed a different approach. The researchers injected mice with cerebrospinal fluid from patients with Parkinson's disease. Over time, the animals developed signs resembling the disease, including accumulations of alpha-synuclein in the brain.
Using the patients' material can help to study the effect of several components simultaneously. The team expects that such a model will allow for a more accurate assessment of potential interventions, although it also remains experimental.
What role can antibodies play?
One of the questions that scientists want to test using the new model concerns the interaction of alpha-synuclein with the immune system. According to the hypothesis of the Zhang group, complexes of pathological protein and autoantibodies can form in the cerebrospinal fluid — antibodies directed against the components of one's own body.
"Our current hypothesis is that it may be an immune complex that includes pathological alpha-synuclein and human autoantibodies. They can form a complex in the cerebrospinal fluid that contributes to the development of the disease," Zhang said.
This assumption still needs to be verified. The very appearance of pathological changes after the introduction of cerebrospinal fluid does not establish which component caused the observed effect.
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