Clearance of TDP-43 by PROteolysis TArgeting Chimera (PROTAC) dual targeting to treat amyotrophic lateral sclerosis (ALS)

The key pathological feature of MND is the presence of abnormal clumps (inclusions) of proteins inside motor neurons – the major component of these inclusions is the protein TDP-43. There is now compelling evidence that TDP-43 inclusions are a major contributor to disease, and therefore many researchers are investigating ways to prevent formation or clear these TDP-43 inclusions. We have recently identified a protein that binds TDP-43 in motor neurons, and we will use this information to construct a therapeutic intervention that combines this with a new technology called PROteolysis TArgeting Chimera (PROTAC). In simple terms our PROTAC will specifically target and clear TDP-43 from neurons, to restore normal cellular function and health. In this project we will perform pre-clinical evaluation of the PROTAC therapy in cell culture experiments.