Grant: Project Grant

Mutations in SMN cause spinal muscular atrophy (SMA), a fatal neurodegenerative disease of infancy. Mutations in many proteins (e.g. senataxin, FUS, and TDP-43) can cause the fatal adult neurodegenerative diseases amyotrophic lateral sclerosis (also known as ALS, or Lou Gehrig's disease) and fronto-temporal dementia (FTD). We have discovered that SMN recognizes a modified form of RNA polymerase II, the enzyme that transcribes human genes, and then engages with senataxin to regulate human gene transcription. Defects in this pathway may lead to neurodegeneration because they lead to altered gene expression or altered DNA structures and resulting DNA damage. It is known that SMN is capable of interacting with FUS, which in turn interacts with TDP-43. Therefore, we will now characterize how FUS and TDP-43 participate in the human gene regulatory pathway that contains RNA polymerase II, SMN, and senataxin, what aspects of human gene expression they regulate, and whether defects in their function also lead to DNA damage. Because TDP-43 function is almost always impaired in ALS and FTD, our experiments should greatly increase understanding of the molecular defects that underpin these devastating diseases and might lead to prevention or treatment in the future.