Grant: Project Grant

TDP-43 is a protein central to neurodegenerative diseases. While mutations in TDP-43 are known to directly contribute to disease, most cases without mutations often show abnormal accumulation of this protein. This suggests that understanding how TDP-43 is regulated in the context of aging, is crucial. Our group recently discovered a link between TDP-43 and a process called SUMOylation, which occurs when small proteins are added to other proteins, altering their behaviour. Following stress, TDP-43 becomes SUMOylated, which led us to create mice with TDP-43 that can't be SUMOylated. Initial studies with these mice suggest that loss of TDP-43 SUMOylation can lead to age-related neurodegenerative features. Furthermore, a new method was developed to detect TDP-43 SUMOylation in postmortem brain and spinal cord tissues, opening possibilities for studying this process in human disease samples. However, it remains unclear how important TDP-43 SUMOylation is for protecting the brain from age-related stress. What's more, we are interested in defining whether SUMOylation plays a broader role in protecting against neurodegeneration, possibly involving other proteins implicated in these age-related disorders. To address these questions, we will longitudinally study the SUMO-deficient mice, examining their behavior, brain tissue, and biochemical markers associated with neurodegeneration. Additionally, they aim to investigate the relationship between TDP-43 SUMOylation and SUMOylation of other proteins involved in neurodegenerative diseases, using advanced techniques to study protein SUMOylation in tissue samples. In sum, this work seeks to unravel the intricate relationship between TDP-43, SUMOylation, aging, and neurodegeneration. By shedding light on these mechanisms, it holds promise for advancing our understanding of neurodegenerative diseases and potentially identifying new therapeutic targets.