With information from Alana Gandra, from Agência Brasil

Researchers at the Federal University of Rio de Janeiro (UFRJ) and the University of Virginia School of Medicine, USA, discovered the early stages of Parkinson’s disease. The study with the conclusion was published last Friday (11) in the journal Communications Biology.

The survey took three years to complete. The next step will be the screening of drugs that block the oligomers (low molecular weight chain-like protein structure), before starting the second phase of animal testing and following the final tests on humans.

Parkinson’s disease is the second most common neurodegenerative disease and can lead to dementia. The first is Alzheimer’s.

Progressive destruction

Neurodegenerative diseases are diseases in which progressive and irreversible destruction of neurons, the cells responsible for the functions of the nervous system, occurs. When this happens, depending on the disease, the patient gradually loses his motor, physiological functions and / or cognitive capacity.

“The big question is what is the target for developing a therapy, a medicine. Our work shows exactly the formation of the so-called competent oligomers, ”said one of the authors of the paper, the researcher at UFRJ, Jerson Lima Silva. “There is evidence that [oligomers] would be our best target.” According to the researcher, Parkinson’s disease affects more than 5 million people worldwide.

These protein structures, when broken, cause the cell to die, and most often when the patient is diagnosed with clinical symptoms, Parkinson’s disease actually began much earlier. “The treatment is palliative. There is no treatment that cures or mitigates the disease, ”said Silva, who is a doctor and professor at the UFRJ Institute of Medical Biochemistry.

The study allowed scientists to observe for the first time how different variants of Parkinson’s disease-associated protein alpha-synuclein interact over time, initially forming these oligomers. From this, and using the familiar mutated form, they were able to identify the initial formation of protein aggregates linked to early cases of the disease.
Lifelong disease

UFRJ professor and doctoral student at the University of Virginia, Guilherme AP de Oliveira, also co-author of the study, said that a person develops Parkinson’s life-long life. “Conversion between protein stages happens slowly and intermediate structures and filaments accumulate for a long time. We do not know which one triggers the onset of symptoms and is more toxic to cells, ”he said. Oliveira said that if researchers can understand the onset of conversion, they could develop therapy for early treatment of the disease.

Silva added that the development of the disease is a slow process and that symptoms usually affect older people. “That’s why the unfamiliar form is common after 65 or 70 years of age.” According to the UFRJ scientist, palliative treatments do not cease the process of formation of oligomers that generate more aggregates, moving from cell to cell. “This is what we have to try to overcome.”

Cutting edge techniques

The researchers used state-of-the-art high-resolution electron microscopy techniques that allow them to see disaggregated proteins at atomic level. “It is important to understand what the target is and what should be used both to develop medicines and perhaps to develop diagnostic methods,” said Silva. The study uses proteins taken from cells and assesses their behavior. The researchers could see that the end product had a difference depending on the mutation. Silva estimates that the project should extend for two or three years.

The researchers compared the formation of the structures in four variants of alpha-synuclein, three of which were linked to early hereditary cases of the disease and one was present in the unmutated cases of aging. They found that in early Parkinson’s cases, the intermediate stages of the aggregation processes of each protein variant formed at a faster rate than in the case of aging. This may explain the onset of symptoms in younger people.

They also found that the amyloid filaments showed distinct structures depending on the protein variant from which they originate. In addition to realizing that the early stages of conversion are distinct, they noted that some filaments formed in early Parkinson’s cases are also different.

Fluorescence

Using the fluorescence technique, the researchers not only viewed the various stages of protein association over time, but also observed structures that were previously unnoticed. Using the technique of electronic cryomicroscopy, which gave its creators the Nobel Prize in Chemistry in 2017, the researchers observed the structural organization of the amyloid filaments.

“Because they [proteins] are very subtle, it was not very clear the separation between what is competent and not competent to generate fiber,” said Silva. Oliveira believes that by seeing such structures, scientists can contribute to the development of new treatments against the disease.

The study was supported by Pew Charitable Trusts, a non-profit non-governmental organization that encourages philanthropy in the underprivileged population of the United States, and was also funded by the Carlos Chagas Filho de Rio de Janeiro State Research Foundation (Faperj), by the National Council for Scientific and Technological Development (CNPq) and by the National Institute of Science and Technology in Structural Biology and Bioimaging (Inbeb).