New project to identify potential treatment targets for MND

18 September 2024

Our 2023 Catalyst Awards are funding bold, early-stage research into MND. Dr. Patrick Lewis of the Royal Veterinary College is one of the three researchers we are funding this year. His work hopes to answer questions about how MND affects our cells at a molecular level.

Researchers have made great strides toward understanding why MND happens, but we don’t have the full picture. In both inherited and sporadic cases of MND, there are gene variants that increase the risk of developing the disease. Scientists have sequenced the genome of people affected by MND to work out what these genes do, allowing these genetic blueprints to be linked to functional changes inside cells.

Understanding the cell’s waste disposal systems

One function repeatedly linked to MND risk is a cellular process called autophagy. This process is essentially a form of waste disposal for the cell. During autophagy, cell waste is tagged, like putting rubbish in your bin; trafficked, like a lorry driving rubbish to a landfill; and then disposed of. Genes that control each of these steps have been linked to MND.

While the impact that these mutations have on cellular waste disposal isn’t fully understood, researchers believe that in MND, this process goes awry. Imagine if all the bin lorries in a city broke down – the streets would quickly fill with rubbish, impacting the rest of the city’s day-to-day function. In cells affected by MND, clumps of protein “waste” fill cells. This accumulation damages and even kills cells. Mutations in autophagy-related genes have been linked to other brain diseases – like Parkinson’s disease.

One important part of the cell’s waste disposal is a protein called tank-binding kinase 1 (TBK1). This protein helps kickstart the autophagy process. Mutations in the TBK1 gene have been linked to both inherited and sporadic MND – this should make it a prime target for studies into the disease.

But research into the gene has been limited. The TBK1 protein modifies other proteins by combining them with other molecules. In conditions like leukaemia, kinases send out modification signals that accelerate disease. Scientists have developed a battery of tools to shut kinases down. However, in MND, TBK1 appears to stop working. Dr. Lewis wants to determine whether MND progression would be slowed or reversed if we turned it back on – this is a more complicated process than adapting one of the many tools available that inhibit kinases.

Mapping out protein interactions

Dr. Lewis’s first task is to understand how TBK1 interacts with other proteins in the cell. These molecules link together in extremely complex networks. While the human genome contains around 20,000 genes, because these can be chopped up and reassembled, the number of proteins that can be made with these genes is far higher. His team will use computational techniques that can track these interactions and build up a picture of all TBK1’s links. Dr. Lewis hopes to find proteins that boost TBK1 – which would provide natural targets for future treatments.

The final stage of Dr. Lewis’s project will involve testing any identified proteins in cellular disease models – to put into biological practice the insights he and his team, including postdoctoral researcher Dr. Noopur Bhore, gain from their computer-based analysis.

We have funded Dr. Lewis with an award of £77,475, which will go toward funding researcher salaries and securing the materials for cellular experiments. The award includes a £40,000 donation from the Tolkien Trust.