Folding, Misfolding and Oligomerization of TDP-43 Life expectancy has been significantly extended through innovation in modern medicine. Ironically, with longevity comes the greater threat of neurodegenerative diseases: chronic, debilitating illnesses with no cures and limited treatments. The World Health Organization has projected neurodegenerative diseases to overtake cancer in the number of annual disease- related deaths by 2040, second only to cardiovascular disease. TDP-43 is a 43 kDa RNA splicing regulator, as well as one of the best biomarkers for several neurodegenerative diseases including Alzheimer?s disease (AD) and amyotrophic lateral sclerosis (ALS). TDP-43 aggregates have been found in 97% of ALS patients and up to 50% of AD patients. The molecular mechanisms of TDP-43 aggregate formation is not well understood; TDP-43 contains an N-terminal oligomerization domain and an intrinsically disordered C- terminal region, both of which are believed to contribute in TDP-43 pathological aggregation. The N-terminal domain has been shown to oligomerize and contribute to TDP-43 self-assembly. This self-assembly is a part of TDP-43 native function in stress granule formation. However, there is speculation that the self-assembly of TDP-43 can lead to aggregation; thus, studying the parameters of N-terminal oligomerization may offer insight into aggregation pathways. TDP-43 is a member of a class of proteins known as intrinsically disordered proteins due to its disordered C-terminal domain. This domain is the site of known mutations and post- translational modifications observed in the brains of patients of neurodegenerative diseases. Cleaved C-terminal domain fragments are also found in patients? brains. In the proposed project, TDP-43 N-terminal and C-terminal domains will be studied using single-molecule and ensemble biophysics techniques to characterize their functions and identify structural switches that are responsible for TDP-43 aggregation.
TDP-43 is strongly implicated in many neurodegenerative diseases including Alzheimer?s disease: aggregates of TDP-43 are seen in the brain of neurodegenerative disease patients. While the mechanism of aggregate formation and its role in pathology is unclear, there is evidence that TDP-43 aggregation is related to protein oligomerization. Studying the switch from TDP-43 oligomerization and function to aggregation and dysfunction will allow us to better understand the mechanisms underlying TDP-43 pathology.
