Targeting mTOR in the CNS

Summary

In MND, normal cell regulatory functions such as degradation and recycling of cellular components (known as autophagy) are impaired resulting in a toxic build-up of proteins. mTOR (mechanistic Target of Rapamycin) is a key protein involved in these processes. When mTOR is too active, the cell undertakes less autophagy, and this contributes to neurodegeneration in MND. There is a lot of evidence showing that drugs targeting mTOR-regulated pathways restore protein clearance and promote neuronal survival in the lab. However, mTOR is in every cell of our body, not just within the central nervous system (CNS). Current drugs that target mTOR are delivered throughout our bodies so could have unwanted side effects. A treatment that lowers mTOR activation in neurons whilst sparing its function in other tissues around the body could lead to a potential treatment for MND. 

Dr Mehta and Dr Farnaby’s team aims to develop treatments that specifically target mTOR in neurons rather than all parts of the body. They will do this by studying a new type of two-headed molecule which has a ‘head’ to target mTOR on one end and a ‘head’ to direct the drug to neurons on the other. Once in location, the treatment will increase the level of autophagy activity in the neurons to clear away harmful proteins, while avoiding the same thing happening in other parts of our bodies where this would be an unwanted side-effect.

Why this research is important 

This work will lay the groundwork for more effective, brain-focused treatments that target mTOR-regulated pathways. Once the drugs have been developed, they will be tested in the lab and if successful, could move forward to clinical trials in people living with MND in the future. Importantly, this work is not tied to any particular genetic form of MND; if successful it would be applicable to the majority, if not all people living with MND.