Parkinson’s disease is associated with toxic clumps of the alpha-synuclein protein in the brain, which disrupt healthy cell communication. Now, a new study shows another way this protein may damage brain cells.
Researchers from Aarhus University in Denmark examined alpha-synuclein oligomers, smaller molecules that also accompany Parkinson’s. Using a lab-made cell model, they found these oligomers can open up tiny pores in cell membranes.
These breaches allow molecules to leak in and out of cells, potentially leading to chemical imbalances that may be a significant driver in the progression of the disease.
Related: Parkinson’s Disease Could Be Ignited by Burned-Out Brain Cells
“We are the first to directly observe how these oligomers form pores – and how the pores behave,” says biophysicist Mette Galsgaard Malle.
“It’s like watching a molecular movie in slow motion.”
The researchers observed a three-step process initiated by the oligomers: attachment, partial insertion, and then pore formation. Once the holes are created, they’re dynamic rather than static, repeatedly opening and closing.
Snapshots of the simulated cell membranes showed how the damage unfolded. Interestingly, the oligomers favored more curved membranes, such as those found in mitochondria, the energy-producing components of the cell. This preference could help explain how these structures work and how to counter the disease.
While this still needs verifying with actual living neurons, we now have a better idea of the mechanisms and how Parkinson’s could be doing its damage.
“This dynamic behavior may help explain why the cells don’t die immediately,” says molecular biologist Bo Volf Brøchner.
“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.”
Parkinson’s is a complex disease, and scientists remain unsure as to what causes it. The harmful protein build-up looked at in this study, for example, could be both a cause and a consequence of the condition.
Alpha-synuclein is essential in a healthy brain, and it’s still unclear why it goes off the rails in Parkinson’s disease. Multiple different risk factors have previously been linked to Parkinson’s, including diet, genetics, and medical history, and they might all be involved in some way.
Like other Parkinson’s studies, this new research not only improves our understanding of the disease, but also points to ways that it might be slowed down or even prevented. The researchers have already tested nanobodies that can identify oligomers after they’re formed, though they don’t yet stop the pores from being created.
Related: Guided Nanoparticles Reconnect Brain Cells, Raising Hopes For Parkinson’s Treatment
It’s a promising step forward in learning more about an aspect of Parkinson’s that hasn’t been extensively studied so far, and the researchers are keen to see if their findings also apply to living brain cells and their proteins as well, before more treatments are explored.
“We created a clean experimental setup where we can measure one thing at a time,” says Malle. “Now we need to take the next step and investigate what happens in more complex biological systems.”
The research has been published in ACS Nano.