The Role of Proteinaceous Fragments in Neurodegeneration

As human lifespan increases, our population faces an increased risk of developing neurodegenerative disease (ND). Most ND are characterized by the aggregation of specific protein fragments within neurons. This work focuses on human TAR DNA-binding protein 43 (TDP43), which has important functions in the regulation of gene expression. During pathological conditions, TDP43 is cleaved giving rise to a variety of nearly identical fragments with

distinct N-termini. Our previous work showed that differences in N- termini influence fragment aggregation and metabolism. Despite a

strong association with ND, it is unclear if toxicity results from the loss of normal TDP43 function upon its cleavage, or from a toxic function acquired by the accumulation and aggregation of its fragments. Using lentiviral-mediated gene delivery, we are expressing TDP43 fragments in cultured primary neurons and specific brain regions in mice that have functional TDP43 to determine if its fragments contribute to ND. (Faculty Sponsor: Dr. Christopher Brower)