Scientists watch a Parkinson's protein pierce neuron membranes for the first time

Scientists have directly watched a Parkinson’s protein punch tiny, shifting holes in lab-grown brain cell membranes for the first time.

The work helps explain how Parkinson’s disease, which affects more than 10 million people worldwide, slowly wears neurons down over many years.

Researchers at Aarhus University built a sensitive imaging setup that tracks single protein attacks on model cell membranes in real time.

They saw small clumps of this protein disturb the barrier in brief episodes, so the membrane leaks without failing outright.

Dangerous Parkinson’s protein

The work was led by Mette Galsgaard Malle, a biophysicist at Aarhus University and Harvard University. Her research focuses on how misfolded proteins damage cell membranes in individuals with brain disorders.

In healthy neurons, the protein alpha synuclein, a flexible protein that helps manage chemical signals, moves near the tiny junctions where cells communicate.

Inside Parkinson’s brains, its shape can shift so it sticks together into dense clumps that crowd the cell interior.

Among these clumps, oligomers – small groups of misfolded protein molecules – seem especially good at harming neurons. Earlier research links these small assemblies to changes in energy use, calcium balance, and survival pathways in Parkinson’s disease neurons.

Three-step attack on the cell

The new study tracked single oligomer particles as they approached simple membrane bubbles in the lab. Researchers saw a three-step sequence; first the particles stick to the surface, then they enter partway, and finally form a pore, or hole, through the membrane.

Once formed, each pore did not stay fixed, it flickered between open and closed states, so molecules crossed gradually rather than all at once.

“We are the first to directly observe how these oligomers form pores and how the pores behave,” said Malle.

The team combined their imaging with tiny electrical recordings that picked up ion flow when an oligomer punched through a flat membrane patch. These signals supported the idea that each opening behaves like a small, well defined channel rather than a messy tear.

A molecular movie in real time

To follow individual events, the group used artificial vesicles, tiny fluid-filled bubbles that mimic cell membranes but without the rest of the cell.

Each vesicle sat on a glass surface, and special dyes inside and outside lit up whenever molecules crossed the boundary.

By tracking hundreds of thousands of vesicles over hours, the researchers could see which membrane types invited pores and which mostly resisted them. 

The activity matched earlier biophysics work showing that alpha synuclein prefers negatively charged, flexible membranes when it disrupts cells.

Small, highly curved vesicles grabbed lots of oligomer particles but often showed little leakage, while larger, flatter ones sprouted more active pores.

Some individual vesicles went through dozens of opening events, which suggests that the same oligomer can switch repeatedly between partial and full insertion.

Mitochondria may be early targets

Many neurons already struggle with their mitochondria, tiny structures that act as power plants for the cell. Recent reviews tie alpha synuclein buildup and mitochondrial failure together as key features of Parkinson’s disease.

In the new experiments, pores appeared most readily in membranes that were rich in negatively charged lipids. This is similar to the membranes found on the surfaces of mitochondria.

Other groups have found that alpha synuclein oligomers can interact with mitochondrial lipids and disturb their function.

Those studies in cell culture research suggest that pore-like openings may directly weaken these energy hubs. If mitochondrial membranes face repeated opening events like this, they could slowly lose control of ions and fuel molecules.

That kind of low-level leak fits with a disease that creeps forward over decades instead of killing neurons overnight.

Lessons from this Parkinson’s protein

The team also tested nanobodies, tiny antibody fragments that bind very specifically to the oligomers. These molecules did not block the openings, but one nanobody made pores more active, while both strongly highlighted the presence of oligomers.

Strong and selective binding like this could someday form the basis of brain scans or blood tests that flag toxic oligomers early. 

Parkinson’s disease is usually diagnosed only after movement symptoms appear, by which time many dopamine-making neurons in the midbrain are already lost.

Drugs that stabilize the protein shape or change how it touches membranes might reduce the number or strength of these pores.

For now, the experiments use simplified model membranes, so the next step is to confirm how this process unfolds in neurons and brain tissue.

As populations age and more people live long enough to face Parkinson’s, understanding how a single protein quietly chips away at neurons becomes crucial.

This new picture of dynamic, reversible pores offers a target for experiments that aim to slow or stop the disease at its earliest stages.

The study is published in ACS Nano.

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