In Parkinson’s disease, dopamine-producing nerve cells in the brain die. This leads to a lack of dopamine, which causes the typical muscle tremors. Despite intensive research, the causes of the disease are still not fully understood. Researchers have now shown that copper ions help a certain protein in the brain, called alpha-synuclein, to clump together. Clumps of this protein have previously been linked to nerve cell death in Parkinson’s disease. The new findings might help to develop early detection tests. They are also a further step on the way to a causal treatment of the disease.
Parkinson’s is the second most common neurodegenerative disease worldwide following Alzheimer’s. Previous therapeutic approaches aim to compensate for the lack of dopamine in the brain with medication. In the early stages, the symptoms can be alleviated. However, the drugs cannot stop the progressive degradation of the nerve cells. A causal treatment is not yet possible because the causes of Parkinson’s have not yet been clarified in detail. Researchers have long suspected that environmental influences such as pesticides contribute to the disease. The vital trace element copper is also discussed as an influencing factor.
Copper suspected
A team led by Olena Synhaivska from the Swiss Federal Laboratories for Materials Testing and Research (Empa) in Dübendorf, Switzerland, has now taken a closer look at the role of copper in the development of Parkinson’s. Copper is ingested through food and fulfills important functions in cell metabolism. Among other things, it plays an important role in bone growth, the transmission of stimuli in nerve cells and hormone production. In the brain, however, it has an ambiguous effect: In relation to Alzheimer’s disease, it has already been discussed as both a risk and a protective factor, and it might also be involved in the development of Parkinson’s disease.
Synhaivska and her colleagues focused on the interactions of copper ions with the protein alpha-synuclein. This protein is normally water-soluble, but is sometimes present in an abnormal, clumped form in people with Parkinson’s disease. In order to find out to what extent copper influences the clumping of alpha-synuclein, the researchers first produced the protein artificially and observed it in the test tube. With the help of atomic force microscopy, they visualized how the protein initially formed individual insoluble threads over the course of the ten-day observation period, which finally clumped together to form a dense network.
Accelerated clumping
In another experimental approach, the researchers added copper ions to the alpha-synuclein solution and observed the effects. “High doses of copper seem to accelerate the aggregation process,” reports Synhaivska’s colleague Peter Nirmalraj. In addition to the protein threads that form more quickly, the researchers discovered another abnormal form of alpha-synuclein in the solution mixed with copper: following just a few hours, ring-shaped structures regarding seven nanometers in size formed. These so-called oligomers have previously been associated with nerve cell damage.
Since the oligomer rings form at the very beginning of the conversion of healthy alpha-synuclein into diseased clumps, Nirmalraj hopes they might be used as a target for new therapeutic approaches. In addition, the findings might help to develop a diagnostic test with which Parkinson’s can be detected in the early stages – for example, if the ring-shaped variant of alpha-synuclein might be detected in samples from the cerebrospinal fluid.
Source: Olena Synhaivska (Federal Materials Testing and Research Institute, Switzerland) et al., ACS Chemical Neuroscience, doi: 10.1021 / acschemneuro.2c00021
