University of Dundee

MRC PPU researchers' chemical technology brings new insight into Parkinson’s disease

07 Mar 2016

Pioneering chemical technology developed at the University of Dundee is giving scientists the clearest insight yet into crucial biochemical processes that are active in many diseases, including Parkinson’s disease.
Dr Satpal Virdee, leader of the research team, said their findings could `revolutionise’ research capability.
Already the Dundee team have used their newly developed tools to make new discoveries relating to the activity of the Parkin enzyme, which when mutated is a cause of Parkinson’s disease.
The results of the research are published in the journal Nature Chemical Biology.
Dundee is one of the world’s leading centres for research into a process called protein ubiquitylation. This is a cellular regulatory mechanism that affects many processes in our cells, and involves the attachment of a small protein called ubiquitin to other proteins.
One of the most significant functions of ubiquitylation is to mark damaged or unwanted proteins for destruction. This is an extremely intricate process – there are thousands of proteins in our cells, and specific ones can be tagged with ubiquitin.
This specificity is achieved by around 600 protein enzymes known as E3s. If an E3 is faulty then this can manifest itself as disease. The difficulty facing scientists has been that measuring the activity of even a single E3 enzyme in the cell has proved challenging.
Now the group at Dundee, led by Dr Virdee, has developed a chemical probe that allows not only a single E3’s activity in a cell to be measured, but, in principle, the activity of dozens of E3s to be measured simultaneously.
“This technology should revolutionise our ability to understand the roles of E3s and protein ubiquitylation in both normal and diseased cells with immediate translational potential to address diseases,” said Dr Virdee, Programme Leader in the Medical Research Council Protein Phosphorylation & Ubiquitylation Unit (MRC-PPU) in the School of Life Sciences at Dundee.
Dr Virdee’s team have tested the technology by looking at an E3 enzyme, Parkin, which when faulty can give rise to Parkinson’s disease.
“We made a number of novel findings around how Parkin is activated in the cell,” said Dr Virdee.
“For the first time our probes enable direct and quantitative measurement of endogenous Parkin activity. Our probes have given new insights into the pathogenic basis for the many patient mutations that are found within Parkin. We have also shown that our technology can potentially be used as a clinical tool to assess the functionality of the Parkin pathway in patients.”
Dr Virdee said the technology breakthrough offer multiple benefits for researchers including:
·         the discovery of new biology
·         discovery of new therapeutic targets
·         as a powerful structural biology tool
·         to discover new drugs and assess their specificity
·         and as a clinical diagnostic tool
The research was carried out in collaboration with Dr Miratul Muqit’s group in the MRC-PPU at Dundee and with colleagues at Sorbonne Universités in Paris.
The work has been funded by the Scottish Funding Council and the Medical Research Council.