With an aging population, neurodegenerative disorders contribute increasingly to our global health burden with no cure or effective treatments. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative disorders that are distinct in clinical presentation (ALS impairs movement/breathing, whereas FTD impairs behavior/cognition). However, they share a common underlying feature – that an essential protein named TDP-43 builds up in clumps inside neurons and loses its normal function. Therefore, a central question in the ALS/FTD field is to determine the consequences of TDP-43 dysfunction. A critical role of TDP-43 is to regulate the length of RNA “tail”– called the 3’ UTR (a region at the end of RNA that is important for determining RNA and protein abundance, location, and function). Thus, I hypothesize that TDP-43 dysfunction causes RNAs to have aberrant tail lengths, which ultimately contributes to neurodegeneration. Supporting this hypothesis, I have found profound changes in the RNA tail lengths in neurons from the brains of patients with these diseases. Thus, in this proposal, my goals are to systematically investigate 1) which RNAs’ tail lengths change upon TDP- 43 dysfunction, 2) why these tail length changes are happening, and 3) if and how these changes contribute to neurodegeneration. To effectively address these questions, I will utilize a multitude of approaches that include stem cell technology, genetic screens, and machine learning. I will also validate my findings in human patient tissues. Ultimately, this proposal will generate exciting new insights into the mechanisms of ALS and FTD and establish novel ways to diagnose and treat these diseases.