Research Projects

The TAR DNA binding Protein of 43 kDa weight (TDP-43) is a vital protein that undergoes aggregation, leading to fatal neurodegenerative disorders like amyotrophic lateral sclerosis (ALS). In ALS cases, 97% of patients show TDP-43 aggregation, indicating a direct link between TDP-43 aggregation and neurodegeneration. However, there is a lack of understanding of how functional TDP-43 converts into large, disease-causing aggregates. Previous studies have examined individual domains of TDP-43 to understand the aggregation mechanism, but the change in the aggregation mechanism when domains are part of the full-length protein is unclear. Residue-level information about structural changes during aggregation is crucial for drug design. The current proposal aims to understand the molecular-level structural changes happening to full-length TDP-43 during its aggregation using spectroscopic techniques and multi-site FRET. This will allow for the capture of initial unfolding and misfolding events during aggregation. The study will also investigate the effects of protein-transfer metals (PTMs) on the aggregation mechanism and investigate intermediate states along the full-length TDP-43 aggregation pathway for cellular toxicity. This will improve the mechanistic and residue-level understanding of the aggregation process of full-length TDP-43, which will be essential for therapeutic interventions.