Tweaked Peptide May Prevent Toxic Alpha-synuclein Clumps From Forming

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A new molecule — a peptide tweaked by scientists in the laboratory — has the potential to prevent the misfolding and toxic aggregation, or clumping, of misfolded alpha-synuclein protein, a hallmark of Parkinson’s disease, a study shows.

This study, supported by funds from Alzheimer’s Research U.K., paves the way for the development of possible therapies to target the root cause of Parkinson’s, according to researchers.

Importantly, this version of the peptide has no impact on the normal function of healthy alpha-synuclein, the scientists noted.

“We’re pleased to have supported this important work to develop a molecule that can stop alpha synuclein from misfolding. The molecule has been tested in cells in the laboratory and will need further development and testing before it can be made into a treatment. This process will take a number of years, but it is a promising discovery that could pave the way for a new drug in future,” Rosa Sancho, PhD, head of research at Alzheimer’s Research U.K., said in a press release.

“Currently there are no disease-modifying treatments available for Parkinson’s disease or dementia with Lewy bodies, which is why continued investment in research is so important for all those living with these diseases,” Sancho added. “Finding ways to stop alpha synuclein from becoming toxic and damaging brain cells could highlight a new pathway for future drugs to stop devastating diseases like Parkinson’s and dementia with Lewy bodies.”

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The study, “A Downsized and Optimised Intracellular Library-Derived Peptide Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without Impacting Upon Lipid Binding,” was published in the Journal of Molecular Biology.

One of the key features of Parkinson’s is the accumulation of toxic clumps of misfolded alpha-synuclein protein, known as Lewy bodies, within dopamine-producing nerve cells — those responsible for releasing the neurotransmitter dopamine — resulting in their death. Dopamine is a chemical messenger that allows nerve cells to communicate and, among other functions, helps regulate movement.

As such, researchers have tried to target misfolded forms of alpha-synuclein to prevent the degeneration that occurs within nerve cells. However, this has proven challenging, especially at preventing the interactions of large proteins such as alpha-synuclein.

In a prior study, researchers at the University of Bath analyzed a library of 209,952 peptides — short chains of amino acids, the building blocks of proteins — in search of a candidate peptide that could prevent alpha-synuclein from misfolding and aggregating into toxic clumps.

“Previous attempts to inhibit alpha synuclein aggregation with small molecule drugs has been unfruitful as they are too small to inhibit such large protein interactions,” said Richard M. Meade of the university’s department of biology and biochemistry, the study’s first author.

“This is why peptides are a good option — because they are big enough to prevent the protein from aggregating but small enough to be used as a drug,” Meade said.

One particular peptide, called 4554W, showed the most promise, being able to block the aggregation of alpha-synuclein into toxic clumps in lab tests with living cells.

Taking the research a step further, the scientists tweaked peptide 4554W to boost its efficacy.

The new tweaked version — called 4654W(N6A) — contains two modifications from the original peptide sequence that were shown to significantly increase its ability to lower alpha-synuclein misfolding, aggregation, and toxicity.

“The effectiveness of the 4654W(N6A) peptide on alpha synuclein aggregation and cell survival in cultures is very exciting, as it highlights that we now know where to target on the alpha synuclein protein to suppress its toxicity,” Meade said.

“Not only will this research lead to the development of new treatments to prevent the disease, but it is also uncovering fundamental mechanisms of the disease itself, furthering our understanding of why the protein misfolds in the first place,” he added.

Importantly, the new peptide didn’t seem to impair the function of healthy alpha-synuclein — specifically, its ability to regulate the release of neurotransmitters, like dopamine. The researchers will now work to develop a peptide that can be tested in human trials.

“Next, we’ll be working to how we can take this peptide to clinic,” said Jody Mason, PhD, the study’s lead researcher and also a professor in the biology and biochemistry department at the University of Bath.

“We need to find ways to modify it further so it’s more drug-like and can cross biological membranes and get into the cells of the brain,” said Mason, the senior author. “This may mean moving away from naturally occurring amino acids towards molecules that are made in the lab.”

Sancho noted that the research is still in the early stages.

“This process will take a number of years, but it is a promising discovery that could pave the way for a new drug in future,” she said.

The scientists said their overarching goal is to find a treatment that targets the root cause of Parkinson’s and can restore patient health before symptoms develop.

“This work paves the way toward the major aim of deriving a highly potent peptide antagonist of [alpha-synuclein] pathogenicity [disease-causing] without impacting on native [alpha-synuclein] function,” the researchers concluded.