Scientists have discovered a genetic mutation associated with protection against Parkinson's disease

Some rare genetic features may not increase, but, on the contrary, reduce susceptibility to neurodegenerative diseases. The researchers found that the APOE Christchurch mutation, which has previously been linked to protection against Alzheimer's disease, may prevent the accumulation of proteins characteristic of Parkinson's disease and dementia with Lewy bodies. So far, this effect has been confirmed in animal experiments. About what happens in the brain with this mutation and why the discovery interested scientists — in the material "Izvestia".

The mutation prevented the accumulation of two proteins in the brain

The study was conducted by specialists from the Oregon Health and Science University in the USA. The results are published in the journal Cell Reports. The scientists studied the rare Christchurch mutation in the APOE gene, which had previously attracted the attention of researchers due to its possible protective role in Alzheimer's disease.

The experiments used genetically modified mice predisposed to the accumulation of pathological proteins in the brain. The researchers introduced the Christchurch mutation into the APOE gene and compared the animals with mice without this genetic feature. As a result, the accumulation of tau protein associated with neurodegenerative changes, as well as alpha-synuclein, a protein whose accumulations are characteristic of Parkinson's disease and dementia with Lewy bodies, decreased in the carriers of the mutation.

The effect on alpha-synuclein was particularly noticeable: the mutation prevented not only the formation of its accumulations in the brain, but also the spread of pathological aggregates. The researchers found a similar protective effect when studying the spread of protein accumulations from peripheral tissues to the spinal cord.

The protective effect was wider than expected

Interest in the Christchurch mutation arose after describing the case of a woman from Colombia who had a hereditary genetic predisposition to Alzheimer's disease, but retained cognitive functions much longer than expected. Subsequently, researchers discovered she had a rare APOE Christchurch mutation. It has been linked to an unusual resistance to the development of dementia, despite the presence of other genetic risk factors.

Subsequent animal experiments have shown that this feature can prevent the accumulation of tau protein. The new work has expanded the understanding of its possible role: scientists have for the first time demonstrated the protective effect of a mutation against alpha-synuclein, one of the key proteins involved in the formation of pathological changes in Parkinson's disease and dementia with Lewy bodies.

How is the mutation related to the work of APOE

The APOE gene is responsible for the production of apolipoprotein E, a protein that is involved in lipid transport and metabolism in the nervous system. Different variants of this gene can have different effects on the likelihood of developing neurodegenerative diseases. For example, the APOE4 variant is associated with an increased risk of Alzheimer's disease, whereas APOE2 has demonstrated protective properties in a number of studies.

The Christchurch mutation is a rare change in the APOE3 gene: at a certain protein position, one amino acid is replaced by another. The researchers suggest that such a rearrangement affects the interaction of apolipoprotein E with other molecules and may complicate the processes necessary for the formation and spread of pathological protein clusters.

Vivek Uni compared the effect of the mutation with the action of APOE2 and called it "super-APOE2". However, this comparison applies to a specific experimental mouse model. This does not mean that in humans, the mutation necessarily provides stronger protection against neurodegenerative diseases.

Scientists talked about a new approach to the fight against Parkinson's disease

It is still a long way from confirming the protective effect in humans.

The researchers believe that the discovery helps to better understand the mechanisms that link the APOE gene to the accumulation of pathological proteins in the nervous system. In the future, this may provide new directions for studying genetic features that can slow down the development of neurodegenerative processes.

Vivek Uni's laboratory plans to continue preclinical studies in order to study the protective properties of the mutation in more detail. According to the scientist, it may take several years for such approaches to be tested in human studies. To do this, it is necessary to confirm the results in additional experimental models and evaluate the possible consequences of changing the operation of APOE.

However, the current work does not prove that the mutation prevents Parkinson's disease or dementia with Lewy bodies in humans. The main conclusions were drawn based on experiments with mice, and the absence of pathological protein accumulations in such a model does not mean that the disease or its symptoms are completely prevented. So far, the study reveals a potentially important mechanism for protecting the nervous system, but there is no reason to talk about a ready-made method of prevention.