Toxicity and Binding of TAR DNA-Binding Protein 43

Present in many neurodegenerative diseases, specifically Amyotrophic Lateral Sclerosis (ALS), is a mutation of the protein TAR DNA-Binding Protein 43 (TDP-43). This protein is key in managing transcription of DNA and shuttling RNA through a cell. When a mutation in this protein occurs, healthy cells, specifically neurons, do not function and usually undergo apoptosis. When this occurs in the motor neurons of a patient, this causes ALS; if this occurs in the central nervous system, then Frontotemporal Dementia occurs. As such, discovering a therapeutic to target the mutation and toxicity of TDP-43 is one of the best methods to aiding patients. Before any drugs can be finalized, an understanding of TDP-43 toxicity is vital. To help characterize the disease qualitatively, toxicity is expressed and rescued using yeast as a neuronal model. After some microbiological work was done to express the toxicity of TDP-43 and the rescue capability of RNA, then biochemical work was conducted to explore the binding of TDP-43, both in dimers and RNA/DNA binding. As seen in the results, TDP-43 is seen to form a dimer, but it is still unclear where the dimerization occurs. Furthermore, TDP-43 does have binding capacity to both DNA and RNA, but further work needs to be done to create a construct of the protein that does not have a tag. Currently, the methods for producing a TDP-43 construct without a tag is currently underway, and this will help model the character of the protein.