Are Scientists Homing in on a Cure for Parkinson’s Disease?

Summary: Researchers have refined a molecule that shows promise for the prevention of Parkinson’s disease.

Source: University of Bath

A molecule that shows promise in preventing Parkinson’s disease has been refined by scientists at the University of Bath in the UK, and has the potential to be developed into a drug to treat the deadly neurodegenerative disease.

Professor Jody Mason, who led the research from the Department of Biology and Biochemistry at Bath, said: “A lot of work still needs to happen, but this molecule has the potential to be a pre-cursor to a drug. Today there are only medicines to treat the symptoms of Parkinson’s—we hope to develop a drug that can return people to good health even before symptoms develop.”

Parkinson’s Disease is characterized by a specific protein in human cells ‘misfolding’, where it becomes aggregated and malfunctions. The protein—alpha-synuclein (αS) – is abundant in all human brains. After misfolding, it accumulates in large masses, known as Lewy bodies.

These masses consist of αS aggregates that are toxic to dopamine-producing brain cells, causing them to die. It is this drop in dopamine signaling that triggers the symptoms of Parkinson’s Disease, as the signals transmitting from the brain to the body become noisy, leading to the distinctive tremors seen in sufferers.

Previous efforts to target and ‘detoxify’ αS-induced neurodegeneration have seen scientists analyze a vast library of peptides (short chains of amino acids—the building blocks of proteins) to find the best candidate for preventing αS misfolding. Of the 209,952 peptides screened in earlier work by scientists at Bath, peptide 4554W showed the most promise, inhibiting αS from aggregating into toxic disease forms in lab experiments in solutions and on live cells.

In their latest work, this same group of scientists tweaked peptide 4554W to optimize its function. The new version of the molecule—4654W(N6A)—contains two modifications to the parental amino-acid sequence and has proven to be significantly more effective at reducing αS misfolding, aggregation and toxicity. However, even if the modified molecule continues to prove successful in lab experiments, a cure for the disease is still many years away.

Dr. Richard Meade, the study lead author, says that “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. 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.

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 supress its toxicity. 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.”

Professor Mason added that “next, we’ll be working to how we can take this peptide to clinic. 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. This may mean moving away from naturally occurring amino acids towards molecules that are made in the lab.”

This shows a finger touching a picture of a brain
In their latest work, this same group of scientists tweaked peptide 4554W to optimize its function. Image is in the public domain

This research also has implications for Alzheimer’s disease, Type 2 diabetes and other serious human diseases where symptoms are triggered by protein misfolding.

Dr. Rosa Sancho, head of research at Alzheimer’s Research UK, said that “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.”

“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.”

“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.”

About this Parkinson’s disease research news

Author: Press Office
Source: University of Bath
Contact: Press Office – University of Bath
Image: The image is in the public domain

Original Research: Closed access.
A Downsized and Optimised Intracellular Library-Derived Peptide Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without Impacting Upon Lipid Binding” by Richard M. Meade et al. Journal of Molecular Biology


A Downsized and Optimised Intracellular Library-Derived Peptide Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without Impacting Upon Lipid Binding

Misfolding and aggregation of alpha-synuclein (αS) within dopaminergic neurons is a key factor in the development and progression of a group of age-related neurodegenerative diseases, termed synucleinopathies, that include Parkinson’s disease (PD). We previously derived a peptide inhibitor from a 209,952-member intracellular library screen by employing the preNAC region (45–54) as a design template.

At least six single-point mutations firmly linked to early-onset Parkinson’s disease (E46K, H50Q, G51D, A53T/E/V) are located within this region, strongly implicating a pathogenic role within αS that leads to increased cytotoxicity. A library-derived ten residue peptide, 4554W, was consequently shown to block αS aggregation at the point of primary nucleation via lipid induction, inhibiting its conversion into downstream cytotoxic species.

Here we couple truncation with a full alanine scan analysis, to establish the effect upon the αS aggregation pathway relative to 4554W. This revealed the precise residues responsible for eliciting inhibitory interaction and function, as well as those potentially amenable to modification or functionalization.

We find that modification N6A combined with N-terminal truncation results in a peptide of significantly increased efficacy. Importantly, our data demonstrate that the peptide does not directly disrupt αS lipid-binding, a desirable trait since antagonists of αS aggregation and toxicity should not impede association with small synaptic neurotransmitter vesicles, and thus not disrupt dopaminergic vesicle fusion and recycling.

This work paves the way toward the major aim of deriving a highly potent peptide antagonist of αS pathogenicity without impacting on native αS function.

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  1. I appreciate that you explained that protein misfolding can trigger symptoms of human disease. I remember when a friend of mine mentioned to me that their family is hoping to find clinical research that can help his brother that has an early stage of Parkinson’s disease and asked if I have any idea what is the best option to do. Thanks to this helpful article, I’ll be sure to tell him that it will be much better if he consults a trusted clinical research company as they can help them with their concerns.

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