Cognitive impairment due to neurodegeneration plagues 20% of the world population by age 65, yet the mechanistic underpinning of pathogenesis is unknown. The abnormal cytosolic accumulation of TDP43 (transactive response DNA binding protein) is found broadly across neurological disorders, including Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD), and Amyotrophic Lateral Sclerosis (ALS). Notably, the severity of TDP43 accumulation correlates with cognitive impairment in neurodegenerative disorders. Therefore, my long-term goal is to determine the relationship between TDP43 function and cognition using integrative multi-omics to improve our understanding of the molecular underpinnings of AD, FTD, and ALS. To determine how TDP43 dysfunction underlies cognitive impairment in FTD and ALS, I am using TurboID- based proximity labelling to identify TDP43 protein interactions in the adult brain of an FTD and ALS mouse model. TDP43 interactions in the healthy adult brain consist of many (~25%) synaptic proteins and TDP43-ribosomal interactions are enriched in synaptosomes. Taken together, this is consistent with previous studies showing TDP43 functions at the synapse by transporting RNA condensates for local translation. I found the presence of TDP43Q331K, a causative mutation of FTD and ALS, enriches synaptic protein-TDP43 interactions. This suggests that the role of synaptic TDP43 may be a key molecular mechanism alteration in FTD and ALS pathogenesis. TDP43’s role in local translation is activity dependent. Therefore, I used the speed of TDP43- TurboID biotinylation to capture changes in TDP43 interactions upon neuronal activity. Neuronal activity induced TDP43-glycolytic enzyme interactions. This is notable because glycolytic enzymes are known to concentrate into RNA dependent condensates upon neuronal activity to enhance energy production at the synapse, and TDP43 is a well-known scaffold for RNA dependent condensate formation. Given glycolytic perturbations are associated with plaque formation, synaptic loss, and cognitive impairment, in the F99 phase of this proposal, I will test the hypothesis that upon neuronal activity, TDP43 acts to create condensates of glycolytic enzymes to enhance glycolysis at the synapse. Additionally, I will determine if TDP43 dependent glycolytic alterations are present in an FTD and ALS mouse model as predicted by glycolytic reductions in FTD and ALS patients. Neuronal activity dependent TDP43 interactions also suggest synaptic TDP43 function may link back to its well-known role in splicing and transcription. In the K00 phase of this proposal, I will use a multi-omic approach to determine if TDP43 relays information from the synapse to the nucleus to regulate gene expression and if dysfunction of this mechanism promotes the splicing and transcriptional alterations seen in FTD and ALS.