What do we know?

A causative agent in the pathology of Parkinson’s and related diseases is α-synuclein (αS), a protein which forms toxic clumps known as Lewy bodies, which interfere with normal brain function and lead to the symptoms of the disease. Despite the cost and number of sufferers, relatively little is understood about how αS deposits form and even less about the inhibitory mechanism of potential therapeutics. Lewy bodies accumulate inside dopamine producing cells in the brain, leading to their death, decreased dopamine levels, and ultimately the symptoms of PD.

What has been found out so far?

To address the gap in knowledge, we are developing peptide (very small protein) inhibitors using a novel system that allows us to screen vast peptide libraries inside living cells and pick out those that can stick to αS and prevent it being toxic.  We combine this approach with biophysical and cell biology-based studies on brain cells to investigate how the selected peptides function to restore brain cell health. The novelty of the approach lies in the fact that selection is undertaken entirely inside cells with no assumptions made about how the peptides work. Rather, the cells can only live if the peptides can stick to aS and stop it from being toxic. This last point is important, as it has hampered the search for drugs able to remove clumps but not toxicity.

The following publications provides a comprehensive background to the subject:

Cheruvara H, Allen-Baume V.L, Kad N.M, Mason J.M. Intracellular screening of a peptide library to derive a potent peptide inhibitor of α-synuclein aggregation. J Biol Chem. 290, 7426-35 (2015).

Mason J.M. & Fairlie D.P. Towards peptide-based inhibitors as therapies for Parkinson's disease Future Med. Chem. 7, 2103-5 (2015).

What next?

The student will test the potency of new peptides and peptide-derived molecules using a range of biophysical, structural, and cell-based experiments. These will identify if our inhibitors work in terms of clumping and toxicity, how much is needed to work, where they bind, if they are stable in human serum and can cross biological membranes, and how they behave in neuronal cell cultures.

Why is this important?

There is currently no cure for Parkinson’s disease. Peptides capable of furthering our understanding of how αS clumping and toxicity are coupled will be identified. We are convinced that our cell based peptide-library approach has considerable potential to accelerate this process.

Further information 

Please click here for more information about the work of Dr Jody Mason

Please click here for more information about the work of Dr Robert Williams

Photo: Researcher Richard Meade