Are scientists homing in on a cure for Parkinson's disease?

Date:
December 9, 2021
Source:
University of Bath
Summary:
A peptide known to prevent the protein error that gives rise to
Parkinson's disease has been optimized by scientists. The new
peptide is a strong candidate for future development into a cure.



FULL STORY ==========================================================================
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 characterised by a specific
protein in human cells 'misfolding', where it becomes aggregated and malfunctions. The protein - - alpha-synuclein (aS) -- is abundant in all
human brains. After misfolding, it accumulates in large masses, known
as Lewy bodies. These masses consist of aS aggregates that are toxic to dopamine-producing brain cells, causing them to die. It is this drop in dopamine signalling 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' aS-induced neurodegeneration
have seen scientists analyse a vast library of peptides (short chains
of amino acids -- the building blocks of proteins) to find the best
candidate for preventing aS misfolding. Of the 209,952 peptides screened
in earlier work by scientists at Bath, peptide 4554W showed the most
promise, inhibiting aS 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 optimise 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 aS 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, said: "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: "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 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:
"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." ========================================================================== Story Source: Materials provided by University_of_Bath. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Richard M. Meade, Kathryn J.C. Watt, Robert J. Williams, Jody
M. Mason. A
Downsized and Optimised Intracellular Library-Derived Peptide
Prevents Alpha-Synuclein Primary Nucleation and Toxicity Without
Impacting Upon Lipid Binding. Journal of Molecular Biology, 2021;
433 (24): 167323 DOI: 10.1016/j.jmb.2021.167323 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211209133929.htm

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