Discovery of ‘Master Controller’ Region of Alpha-Synuclein Aggregation Opens Door to New Therapies

Scientists have discovered a “master controller” region that regulates aggregation of the alpha-synuclein protein, one of the distinctive features of Parkinson’s disease that is known to lead to the progressive degeneration of brain cells.

Understanding how the master controller works opens new opportunities in both the design of new therapies and in understanding the disease itself.

The findings were reported in the study, “A short motif in the N-terminal region of α-synuclein is critical for both aggregation and function,” published in the peer-reviewed journal Nature Structural and Molecular Biology.

Alpha-synuclein is found mainly in neurons, where, although its precise role remains unknown, it appears to be involved in neuron communication. However, in Parkinson’s, toxic clumps of alpha-synuclein — known as amyloid, or Lewy bodies — form, contributing to the onset and progression of the disease.

Previous studies have shown that a central region of the alpha-synuclein protein called NAC plays a key role in protein aggregation. However, less is known about the role other portions of the protein surrounding NAC may play in the process.

Now, researchers at the Astbury Centre for Structural Biology in the U.K. found two regions outside of NAC, called P1 and P2, that act as “master controllers” of alpha-synuclein aggregation.

In their experiments they showed that when they deleted or replaced both regions, alpha-synuclein was no longer able to form aggregates, even though NAC remained intact. Although these in vitro experiments established the biochemical importance of P1 and P2, further tests needed to be done to assess whether the same results could be found in living cells and organisms.

To that end, they inserted copies of alpha-synuclein lacking P1 and P2 into the muscle cells of the round worm C. elegans, a common animal model for neurological disorders.

After doing so, they found that while worms that had the normal, or wild-type version, of alpha-synuclein developed the typical toxic protein aggregates as they became older, animals lacking only the P1, or both master controller regions, did not.

These effects also were reflected in the worms’ behavior. Worms carrying the altered protein lacking either only P1 or both P1 and P2, were as mobile as healthy unmodified animals. In contrast, those carrying the version of alpha-synuclein with both master controller regions intact, showed age-dependent declines in motility.

“Our discovery of master controller regions may open up new opportunities to understand how mutating the protein sequence that causes disease could help us find the Achilles heel for these proteins to target for future therapeutic intervention,” Sheena Radford, PhD, co-author of the study said in a press release. Radford is director of the Astbury Centre for Structural Molecular Biology at the University of Leeds.

During neurotransmission, chemical messengers called neurotransmitters are wrapped up in a balloon-like membrane (vesicle), which then fuses with the nerve cell membrane in order to release its contents and propagate the message. Alpha-synuclein is thought to facilitate this process of membrane fusion. (Neurotransmission is the process by which neurons communicate with each other.)

Since P1 and P2 are both located in a region of alpha-synuclein that is responsible for interacting with cell membranes, researchers then wondered what the impact would be of eliminating these regions on alpha-synuclein’s ability to facilitate signaling between neurons.

They found that removing these master control regions interfered with the normal process of membrane fusion, impairing neurotransmission.

So, attempts to use the master control region therapeutically will have to balance the beneficial effects of preventing alpha-synuclein aggregation and the negative effects of compromising neuron communication.

“Our hope is that future research might target this master controller, to allow the development of a therapy which could tweak the conformation or stickiness of alpha-synuclein in the brain with only minimal changes to its function,” said David Brockwell, PhD, also a co-author of the study.

“We hope that such a strategy might be able to help people with early signs of Parkinson’s, by reducing the formation of amyloid plaques in the brain, and to delay the progression of the disease,” Brockwell said.