Tiny holes in brain cells may unlock the mystery of Parkinson’s

Microscopic pores in brain cells may hold vital clues to Parkinson’s disease. Scientists have tracked these disruptions in real time, revealing how toxic protein clusters interact with membranes.

The findings point toward a new explanation for how Parkinson’s symptoms develop, beginning at the molecular level of cell membranes.

The quiet onset of Parkinson’s

Parkinson’s often begins quietly. A tremor in the hand, a stiffness in movement, or slowed responses mark the earliest signs.

Beneath these symptoms lies a gradual loss of brain cells. For decades, the trigger behind this degeneration remained unclear. Now, the focus has shifted to α-synuclein, a protein abundant in nerve cells.

In its healthy state, α-synuclein supports communication between neurons. In Parkinson’s, it misfolds and forms clumps.

Earlier studies focused on fibrils, the large clumps seen in brain tissue. The new research highlights oligomers, smaller assemblies that prove more toxic because of their ability to pierce cell membranes.

Proteins create shifting pores

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

Oligomers do not create static damage. Instead, they attach to curved membrane regions, insert partly, and then complete pores that open and close like revolving doors.

“This dynamic behavior may help explain why the cells don’t die immediately,” said 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.”

Watching molecules move

To capture this activity, the researchers used a single-vesicle analysis platform. These vesicles, artificial bubbles resembling cell membranes, allowed scientists to record oligomer activity in real time.

The team even watched fluorescent dyes move through pores, confirming that molecules can cross once pores form.

“It’s like watching a molecular movie in slow motion,” explained 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.”

Distinct steps of Parkinson’s

The team proposes a three-stage model: initial recruitment to membranes, partial insertion, and full pore formation.

Interestingly, recruitment occurs more often on curved membranes, while full pore creation favors flatter ones. This means the first and final steps are distinct processes shaped by membrane geometry and charge.

Negatively charged lipids, abundant in mitochondria and synaptic vesicles, seem particularly vulnerable. This supports the idea that energy-producing cell regions may be among the first harmed in Parkinson’s.

Pore formation and cell risk

The studies also show that neutral membranes can recruit oligomers, but only negative charges activate pores. Recruitment is enhanced by curvature, likely because tightly bent membranes expose more defects that oligomers can latch onto.

Yet, pore formation itself works best on flat, low-curvature membranes, which offer more stability for the pore to open fully.

This separation between binding and pore creation clarifies earlier contradictions in research. It suggests that cells might not be equally at risk, depending on membrane composition and shape.

Nanobodies and detection

The researchers also tested nanobodies, tiny antibody fragments that bind specifically to oligomers. These nanobodies did not block pore formation, but they helped reveal how pores change dynamics.

One nanobody increased pore turnover, making oligomers more flexible and interactive, while another reduced activity.

“The nanobodies did not block the pore formation,” said 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.”

Implications beyond Parkinson’s

These findings may apply beyond Parkinson’s. The same methods could explore other protein aggregates, such as tau in Alzheimer’s disease, which may also damage membranes in subtle but progressive ways.

The single-vesicle platform offers a high-resolution way to track protein-membrane interactions across different neurodegenerative conditions.

For now, these experiments remain in artificial models. Real brain cells are far more complex, with diverse lipids and interacting proteins. The next challenge is to confirm whether pores form in living tissue and how they contribute to cell death.

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

The study is published in the journal ACS Nano.

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