Grant: Canada Postdoctoral Research Award (CPRA) program

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) form a spectrum of incurable neurodegenerative diseases that are associated with a combination of motor and cognitive symptoms. Pathological evidence places Tar DNA-binding protein 43 (TDP-43) at the epicenter of ALS/FTD pathogenesis. TDP-43 normally resides in the nucleus, where it performs a diverse set of functions. In the majority of ALS/FTD cases, however, TDP-43 is lost from the nucleus and instead forms aggregates in the cytosol. Although TDP-43 aggregates have historically been used as an indicator of disease, mounting evidence suggests that loss of function of TDP-43 is a major driver of neurodegeneration in ALS/FTD. Thus, I intend to investigate the regulation of normal TDP-43 function to provide new, promising avenues for therapeutic intervention in ALS/FTD. TDP-43 is modified by a protein called SUMO2 through a process called SUMOylation. TDP-43 SUMOylation occurs extensively in the central nervous system of aged mice and in ALS/FTD patients. When TDP-43 SUMOylation is impaired, mice develop cognitive defects associated with TDP-43 aggregation in the central nervous system, similar to the phenotypes seen in ALS/FTD patients. These findings led me to hypothesize that TDP-43 SUMOylation regulates neuronal health and function in response to stress and ageing, and the disruption of TDP-43 SUMOylation contributes to ALS/FTD pathogenesis. In testing this hypothesis, I will describe the prevalence of TDP-43 SUMOylation in the central nervous systems of a diverse set of ALS/FTD mouse models and in ALS/FTD patients. Furthermore, I will investigate the mechanisms that lead to TDP-43 SUMOylation and the functional outcomes of TDP-43 SUMOylation in neurons. This work will highlight TDP-43 SUMOylation as an innovative and actionable therapeutic target that can alleviate neurotoxicity in ALS/FTD.