Researchers uncover new neurodegeneration drug target

A research team led by the University of Dundee’s Dr Satpal Virdee has identified a potential new strategy for treating a range of neurodegenerative diseases and neurological disorders for which there are limited treatments. 

The Virdee lab, in collaboration with colleagues at the University of Cambridge, have established the inner workings of an enzyme called MYCBP2 and shown how its activity promotes the self-destruction of axons after injury. Their findings open the possibility of developing drugs that inhibit the enzyme’s activity, thereby providing therapies for diseases such as motor neurone disease, Parkinson’s and multiple sclerosis. 

The team discovered in molecular detail how this unusual enzyme works. They also showed for the first time that a pivotal catalytic step undertaken by MYCBP2 promotes neuron growth during early development, but also axon degeneration in response to nerve injury.

As nerve injury occurs in the early stages of many neurodegenerative diseases and after cancer therapy, blocking MYCBP2 enzyme activity might prove an effective strategy for treating a range of diseases and neuropathies. 

“There is huge unmet clinical need for neurodegenerative diseases and neurological disorders and there is also no way of limiting the nerve damage often associated with the administration of cancer drugs,” said Dr Satpal Virdee, programme leader at the Medical Research Council Protein Phosphorylation Unit (MRC-PPU) at the University of Dundee. 

“Unfortunately, there has been a paucity of enzymes that have been experimentally validated as promising drug targets. Excitingly, the obtained structural and molecular insights might be leveraged to develop novel therapeutic agents thereby helping to address this unmet clinical need. 

“Blocking an enzyme’s activity with a small molecule drug is a tried and tested strategy for treating disease. A problem with neurodegenerative diseases is that very few enzymes whose activity drives the degenerative process have been identified. Furthermore, the features of an enzyme that successfully engage a drug molecule are often shared by related enzymes.  

“This makes it extremely challenging to develop specific drugs and is one of the reasons why many drugs have undesirable side effects. This study provides structural and molecular detail on the mechanism of MYCBP2 enzyme activity, while the seemingly unique mechanism of MYCBP2 should greatly facilitate the development of drugs that are highly specific against it.” 

MYCBP2 belongs to a large family of enzymes known as E3 ligases. E3 ligases attach a small protein called ubiquitin to protein substrates. This marks them for degradation by the cell’s protein recycling machinery, a highly important process in health and disease. In 2018 the Virdee lab used chemical probes they had developed to search out the cell for undiscovered E3 ligases. 

They went on to show that the protein MYCBP2 contains an entirely new class of E3 ligase machinery they termed RING-Cys-Relay. Other labs had shown that if MYCBP2 is removed from animals entirely then it has a neuroprotective effect in models of axon injury. The new study set out to establish in molecular detail the inner workings of MYCBP2’s RING-Cys-Relay activity, and, determine whether loss of RING-Cys-Relay E3 ligase machinery specifically confers neuroprotection. 

Using their mouse model of neurodegeneration, activity-based probes, and structural data, the Virdee group is now in an excellent position to develop and test inhibitors of the RING-Cys-Relay E3 machinery.  

Dr Virdee’s team is based at the Medical Research Council Protein Phosphorylation and Ubiquitylation Unit within Dundee’s School of Life Sciences. They were supported in this research by the Coleman lab at the John van Geest Centre for Brain Repair, Cambridge. 

Their paper is published today in Nature Chemical Biology. 

The study was funded by the UK Medical Research Council, Biotechnology and Biological Sciences Research Council, and the Wellcome Trust.