Alpha-synuclein is a protein naturally found mainly in brain cells (neurons) where it regulates the release of neurotransmitters such as dopamine, allowing communication between the neurons.

In Parkinson’s disease, this protein sticks together into toxic clumps that cause nerve cell death and leads to patients suffering from symptoms such as tremors, difficulties moving and muscle stiffness. Whilst there are treatments available to relieve symptoms, there is currently no cure.

Normally, alpha-synuclein’s natural or “native state” is like a flexible strand, but when active it shapes itself into a helix, which is critical for its function in binding and transporting parcels of dopamine.

The team engineered a peptide fragment that locks alpha-synuclein into its healthy shape, blocking its conversion into the toxic clumps that cause nerve cell death.

Laboratory tests showed the peptide is stable, penetrates brain-like cells, and restores movement while reducing protein deposits in a worm model of Parkinson’s.

This breakthrough, published in the journal JACS Au, demonstrates the potential of rational peptide design to transform large, unstable proteins into compact drug-like molecules.

The findings mark a significant step towards developing new peptide-based treatments for currently untreatable neurodegenerative conditions. Professor Jody Mason, from the Department of Life Sciences at the University of Bath, said: “Our work shows that it is possible to rationally design small peptides that not only prevent harmful protein aggregation but also function inside living systems.

“This opens an exciting path towards new therapies for Parkinson’s and related diseases, where treatment options remain extremely limited.”

Dr Julia Dudley, Head of Research at Alzheimer’s Research UK, which funded the research, said:

“Dementia isn’t an inevitable part of ageing; it’s caused by diseases like Alzheimer’s. To make progress towards a cure for all forms of dementia, we need research focused on developing a broad range of treatments that can slow, stop and ultimately reverse these diseases.

“Although this is early research in an animal model, it’s exciting to see that this new molecule can prevent the build-up of misfolded alpha-synuclein.

“By stabilizing alpha-synuclein in its healthy form, this could open the door to a new class of treatments that could slow progression in diseases like Parkinson’s and dementia with Lewy bodies. We look forward to seeing this research taken to the next stage, potentially exploring how it would work in people.

“We’re delighted to see such promising advances from Alzheimer’s Research UK funded work opening up new avenues for treatments of the future, and the potential to change the lives of those affected by neurodegenerative diseases.”

Further research is needed, but the team hopes that continued progress will enable these and similar molecules to advance towards clinical testing in the coming years.

Rosemari Otton led the studies from the Interdisciplinary Graduate Program in Health Sciences at Cruzeiro do Sul University in São Paulo, Brazil. The scientist, who has dedicated more than 15 years to green tea research, explains that her initial motivation came from curiosity about the truth behind the popular belief that the drink aids in weight loss. The results of her most recent study were published in the journal Cell Biochemistry & Function.

To study the effects of green tea on obesity, the research team fed mice a high-calorie diet for four weeks, with both fat and what they call a “cafeteria diet,” which mimics the Western diet. “We give them chocolate, filled cookies, dulce de leche, condensed milk… In other words, the same type of food that many people consume on a daily basis,” says Otton.

After this initial phase, the animals underwent the green tea experiment for another 12 weeks. During this period, they continued on the high-calorie diet, but some of them began receiving standardized green tea extract at a dose of 500 mg per kilogram of body weight, administered intragastrically (via gavage).

“It’s a method that ensures they all receive the exact dose we want to study. If we put it in water, for example, we’d have no way of knowing how much the animal actually ingested,” says the researcher. For humans, this amount would be equivalent to consuming about 3 grams of green tea per day, or three cups.

However, according to the researcher, not all commercial green tea meets the necessary quality standards. “Ready-made tea bags do not always guarantee the quantity or quality of the compounds. The ideal for consumption would be to use standardized green tea extract, like those found in compounding pharmacies. This is a concentrated way of using the plant, with a guarantee of the presence of flavonoids, which are the health-beneficial compounds present in the green tea plant,” Otton points out.

One methodological difference in the study was the controlled room temperature. The animals were kept in a thermoneutral environment (28 °C) throughout the experiment. Animal facilities generally maintain an average temperature of 22 °C, which represents chronic cold for mice.

“Excessive cold activates compensatory regulatory mechanisms in the animals’ bodies, causing them to expend more energy to stay warm. This can mask the real effects of any substance,” explains the researcher. “If the animals are in a colder environment, the effect of the tea is enhanced by the activation of energy expenditure due to the cold. But by maintaining thermoneutrality, we were able to see the effects of green tea in a ‘clean’ way, without environmental interference,” she explains.

A previous study published in August 2022 in the European Journal of Nutrition found that obese mice treated with green tea experienced a reduction of up to 30% in body weight. “If a person loses 5% to 10% of their body weight, that’s already a lot. So this result in animals is very significant,” says the professor.

Muscular effect

Another highlight of the most recent study was the preservation of muscle morphology. Obesity typically causes a reduction in muscle fiber diameter, but green tea prevented this muscle atrophy. “One way to assess muscle function is to look at fiber diameter. If it increases, we have more active muscle components. Green tea managed to maintain this diameter, showing that it protects muscle against the harmful effects of obesity,” Otton explains.

In addition to morphological data, the researchers evaluated the expression of genes related to glucose metabolism. Treatment with green tea increased the expression of Insr, Irs1, Glut4, Hk1, and Pi3k – genes that are important for glucose uptake and use in muscles. The activity of lactate dehydrogenase (LDH), an enzyme that is essential for glucose metabolism, was also restored.

According to Otton, there is evidence indicating that green tea does not affect the weight of lean animals, suggesting that it acts selectively against excess body fat. “It makes obese animals lose weight but keeps lean animals at a balanced weight. This shows that the tea seems to need an environment with excess nutrients to act, which supports the hypothesis that it acts directly on fat cells.”

Another aspect investigated by the team was the action of the compounds in isolation. “Green tea is a complex matrix with dozens of bioactive compounds. We’ve tried to separate these compounds and study their effects individually, but the whole extract is always more effective. There’s a synergy between the compounds that we can’t reproduce when they’re isolated,” she says.

According to the scientist, one hypothesis explaining the mechanism by which green tea affects obesity involves adiponectin, a protein produced by adipocytes that has anti-inflammatory and metabolic regulation functions. “We conducted a study with adiponectin-knockout mice, meaning they don’t produce it. And in these animals, green tea had no effect. This suggests that adiponectin is a key player in the mechanism of action of the tea,” she comments.

Real-life effects

Despite the encouraging results of the mouse study, Otton points out that it is not yet possible to determine a safe and effective dose of green tea for humans. This is mainly due to the variability of the extracts and the fact that each person behaves differently. “The ideal is chronic consumption, as we see in Asian countries. In Japan, for example, people consume green tea every day, throughout their lives, and obesity rates are low. But this is different from drinking tea for five months and expecting a miraculous weight loss effect,” she ponders.

The researcher argues that natural and accessible treatments should gain ground in the fight against obesity, especially as alternatives to expensive medications that often have side effects. “The idea is to have safe, natural, effective, and high-quality compounds. The Camellia sinensis plant offers this. We’re still studying all the compounds involved, but there’s no doubt that green tea, as a plant matrix rich in flavonoids, has important therapeutic potential.”

The researcher emphasizes that science always seeks to develop practical solutions. “What we see in animals doesn’t always reproduce in humans. But if we want to make this translation to real life, we need to think about all the details, such as ambient temperature. It’s these precautions that increase the validity of our data. We’re far from having all the answers, but we’re getting closer and closer.”