The accumulation of alpha-synuclein proteins in the brain is the culprit behind the neurogenerative disorder in Parkinson's disease. Current knowledge cannot explain wholly how alpha-synuclein works, but with its impact in neurogenerative diseases, scientists aim to broaden the knowledge scope on Parkinson's disease and find new treatment methods.
Lead authors Elizabeth Rhodes and Melissa Birol discovered that the coupling of alpha-synuclein and extracellular glycoproteins results in easier removal of the protein by the neurons. They also identified a key regulator, neurexin 1β, as a potential therapeutic agent. Their findings were published in the journal PLOS Biology.
Aggregates or clusters of alpha-synuclein proteins form a neuron. This one possible model for the pathology of Parkinson's disease. Cell death and the release of alpha-synuclein clusters result after this event. The process of the movement of alpha-synuclein between neurons in the brain is a determinant when it comes to understanding the typical progression patterns of neurogenerative diseases.
A previous study showed the existence of a glycan-binding site on alpha-synuclein. The present study was able to show how alpha-synuclein interacts with cell membranes Via the protein-membrane interaction studies by Birol.
Specific glycans from the cell surface were removed enzymatically to determine how their presence or absence affects the manner how alpha-synuclein was taken up by neurons. There was a decrease in the amount of alpha-synuclein clusters obtained by the cells during the removal of glycans.
The analysis of giant plasma membrane vesicles showed that there were a similar protein and lipid composition from the synthetic membranes obtained from components of real cells. The researcher was able to determine alpha-synuclein and glycans' physical interactions. "There's a structural basis for the alpha-synuclein binding to the glycan, and when the glycans are removed, it changes the nature of the interaction of alpha-synuclein with the cell membrane," explains Rhoades.
The less-frequently studied the acetylated form of alpha-synuclein proteins that are present in both healthy and diseased neurons was the focus of this research. Findings showed that the acetylated form was more effective at forming groups of proteins inside neurons and was needed in glycan interactions.
"No one's really stressed the importance of these acetylated versions," Birol says. "Generally, we need to take a step back in trying to understand how this protein may be propagating between cells, and I think glycans could be an aspect."
"Rhoades and Birol say that the most unexpected finding was the discovery of neurexin 1β as a potential partner in how alpha-synuclein is taken up by neurons. They hope that future research on this presynaptic protein could provide insights into new treatment strategies for Parkinson's and other neurodegenerative diseases, " according to Phys.
The aim of future studies is to gain higher-resolution structural information of alpha-synuclein proteins bound to glycans. It is aimed that future studies will focus on alpha-synuclein acetylation and the role of glycans in the progression of Parkinson's disease.
"Some cells spontaneously internalize these [alpha-synuclein] proteins and some do not. It has generally been assumed that there are alpha-synuclein specific receptors on the cells that do internalize aggregates. That may or may not be true, but [our study] suggests that it's not just the protein receptors but the glycans that are also important," says Rhoades.
