Parkinson’s disease often begins subtly. A slight tremor in the hand. A bit of stiffness. But over time, brain cells begin to die, and the symptoms worsen. The cause has long remained a mystery – but scientists may now be a step closer to an explanation.

At the center of attention is the protein α-synuclein, which plays a role in cell-to-cell communication in the healthy brain. In Parkinson’s, however, it starts to behave abnormally and clumps into toxic structures.

Until now, most research has focused on the large aggregates known as fibrils, which are visible in brain tissue from patients with Parkinson’s. But a new study focuses on smaller, less understood, and more toxic structures: α-synuclein oligomers. According to the researchers, these are the ones that drill microscopic holes in the membranes of nerve cells.

The study was recently published in the prestigious journal ACS Nano, published by the American Chemical Society.

Tiny revolving doors in the cells

“We are the first to directly observe how these oligomers form pores – and how the pores behave,” says Mette Galsgaard Malle, postdoctoral researcher at both Aarhus University and Harvard University.

The process unfolds in three steps. First, the oligomers attach to the membrane, especially at curved regions. Then they partially insert themselves into the membrane. Finally, they form a pore that allows molecules to pass through and potentially disrupt the cell’s internal balance.

But these are not static holes. The pores constantly open and close like tiny revolving doors.

“This dynamic behavior may help explain why the cells don’t die immediately,” says Bo Volf Brøchner, PhD student and first author of the study. “If the pores remained open, the cells would likely collapse very quickly. But because they open and close, the cell’s own pumps might be able to temporarily compensate.”

Molecular movie in slow motion

This is the first time such pore dynamics have been observed in real time. It was made possible by a newly developed single-vesicle analysis platform that allows researchers to follow interactions between individual proteins and individual vesicles.

Vesicles are small artificial bubbles that mimic cell membranes and serve as simplified models of real cells.

“It’s like watching a molecular movie in slow motion,” explains Mette Galsgaard Malle. “Not only can we see what happens – we can also test how different molecules affect the process. That makes the platform a valuable tool for drug screening.”

Long road to treatment

In fact, the team has already tested nanobodies – small antibody fragments – developed to specifically bind these oligomers. They show promise as highly selective diagnostic tools. However, as a treatment, there is still some way to go.

“The nanobodies did not block the pore formation,” says Bo Volf Brøchner. “But they may still help detect oligomers at very early stages of the disease. That’s crucial, since Parkinson’s is typically diagnosed only after significant neuronal damage has occurred.”

The study also shows that the pores are not formed randomly. They tend to emerge in specific membrane types – especially those resembling the membranes of mitochondria, the cell’s energy factories. This could indicate that the damage begins there.

One step at a time

However, the researchers emphasise that the study was conducted in model systems – not in living cells. The next step will be to replicate the findings in biological tissue, where more complex factors come into play.

“We created a clean experimental setup where we can measure one thing at a time. That’s the strength of this platform,” says Mette Galsgaard Malle. “But now we need to take the next step and investigate what happens in more complex biological systems.”

The researchers showed that the core would need to be made of 3.8% carbon for it to have begun crystallizing. This result indicates that carbon may be more abundant in Earth’s core than previously thought, and that this element could have played a key role in how it froze, offering a rare glimpse into the processes occurring at the heart of our planet.

Earth’s inner core, the solid iron-rich mass at the center of our planet, is slowly growing as the surrounding molten outer core cools and freezes. But this process has been a source of debate amongst scientists for decades.

Inner core formation is not just a matter of determining when the core cooled to its freezing point, but instead involves the process of crystallization which depends on its exact chemical composition. Like water droplets in clouds, which can cool to -30 °C before forming hail, molten iron must be supercooled (cooled to below its melting point) before it can freeze.

Previous calculations have suggested that 800-1000 °C of supercooling would be needed to initiate freezing of the core if it were made of pure iron.

However, if the core is supercooled to this degree, researchers have shown that the inner core would grow massively, and the Earth’s magnetic field would fail. But neither of these outcomes have occurred during our planet’s history. Instead, scientists believe that in the past, the core could have cooled to no more than about 250 ^°C below its melting point.

This new research aimed to understand how the inner core exists as observed today with such limited supercooling in the past. Without direct access to the Earth’s deep interior, the research team needed to rely on computer simulations of the freezing process.

They looked at the presence of other elements, specifically silicon, sulphur, oxygen, and carbon, and how these might affect the freezing process.

“Each of these elements exist in the overlying mantle and could therefore have been dissolved into the core during Earth’s history,” explained co-author Associate Professor Andrew Walker (Department of Earth Sciences, University of Oxford). “As a result, these could explain why we have a solid inner core with relatively little supercooling at this depth. The presence of one or more of these elements could also rationalise why the core is less dense than pure iron, a key observation from seismology.”

Using atomic-scale computer simulations of around 100,000 atoms at supercooled temperatures and pressures equivalent to those in the inner core, the research team tracked how often small crystal-like clusters of atoms formed from a liquid. These “nucleation” events are the first steps toward freezing.

What they found was surprising: silicon and sulphur, elements often assumed to be present in the core, actually slow down the freezing process. In other words, more supercooling would be needed to start forming the inner core if these elements were abundant in that part of the Earth.

On the other hand, they found that carbon helped to accelerate freezing in the simulation.

In the study, the researchers tested how much supercooling would be required to freeze the inner core if 2.4% of the core’s mass were made of carbon. The result: about 420 ^°C, still too high, but the closest result to viability yet.

But when they extrapolated their results to a case where 3.8% of the core’s mass is carbon, the required supercooling dropped to 266 ^°C. This is the only known composition that could explain both the nucleation and observed size of the inner core.

This result indicates that carbon may be more abundant in Earth’s core than previously thought, and that without this element, the formation of a solid inner core may never have happened.

The experiments also show that inner core freezing was possible with just the right chemistry, and unlike water when it forms hail, it did so without “nucleation seeds,” tiny particles which help to initiate freezing. This is vital, because when tested in previous simulations, all of the candidates for nucleation seeds in the core have melted or dissolved.

Lead author Dr Alfred Wilson (School of Earth and Environment, University of Leeds) said: “It is exciting to see how atomic scale processes control the fundamental structure and dynamics of our planet. By studying how Earth’s inner core formed, we are not just learning about our planet’s past. We’re getting a rare glimpse into the chemistry of a region we can never hope to reach directly and learning about how it could change in the future.”

Scientists have debated when the inner core began to solidify for decades, with some arguing for an ancient inner core (with freezing beginning more than two billion years ago) and others suggesting a much younger age (less than half a billion years). With this new information about the carbon content of the core, we are one step closer to constraining its chemistry and physical properties, and therefore how it evolved.

The work was funded by the Natural Environment Research Council (NERC).