Investigating TDP-43 palmitoylation as a therapeutic target to lower protein aggregation

In over 97 per cent of all ALS cases a protein called TDP-43, which is normally found within the nucleus of a cell, becomes trapped outside in the cytoplasm where it forms clumps or aggregates. While mutations in the TDP-43 gene are responsible for this dysfunction in a small subset of cases, the cause for most people living with ALS still unknown.

With this award, Lucia aims to characterize the role that palmitoylation may play in TDP-43 dysfunction. Palmitoylation involves the addition of a small tag to a protein that can influence how it functions and where it’s located within a cell. Preliminary results show that TDP-43 is palmitoylated in cells and that this may contribute to the cytoplasmic buildup and aggregation often seen in ALS.

Using both cellular and animal models, Lucia will determine the locations where palmitoylation occurs on TDP-43, as well as what enzymes play a role in the process. She will also explore the relationship between palmitoylation and another common protein modification, called nitrosylation, to better understand how these two processes may influence one another and contribute to ALS.

Understanding how TDP-43 dysfunction could be regulated through palmitoylation is of great interest as the outcomes of this work could contribute to our understanding of almost all cases of ALS and potentially open new avenues of exploration for developing future ALS treatments.