Prof Tom Gillingwater

University of Edinburgh,

There is considerable evidence from human patients and animal models that one of the earliest events occurring in ALS is disruption of the point of connection between a lower motor neurone (nerve fibre) and the muscles it innervates, at sites known as neuromuscular junctions (NMJs). This event renders motor neurones useless as they are no longer able to make muscle contract. And yet, at present it is not possible to study nerve and muscle connectivity at the NMJ in any great detail using human tissue.

This project will take advantage of cutting edge stem cell technology to allow us to grow human nerve and muscle cells in a dish, where we can then induce them to form connections with one another resulting in the creation of NMJs. This new approach will allow us to test the role of an important ALS-causing gene mutations (known as FUS) in regulating how nerve and muscle connect to one another at the NMJ, using a combination of imaging techniques (e.g. microscopy) and molecular biology (e.g. profiling changes in protein expression).

This project will provide important insights into how these gene mutations disrupt nerve and muscle in ALS, highlighting critical events occurring in nerve and muscle that need to be targeted in the development of new therapeutic approaches. We already have an excellent student lined up to undertake these experiments and have established the core underpinning technology around stem cell (iPS) generation and neural specification. The proposal also brings together two research groups with complementary expertise in NMJ biology and stem cells.