Examining tau's interaction with the NOS1 gene promoter

Saidah Lerman, James Madison University

Abstract

Alzheimer’s disease (AD) is a devastating illness that is characterized in part by the buildup of neurofibrillary tangles (NFTs) which are constituted by a misfolded protein called tubulin associated unit, or tau. During disease progression, AD patients also see changes in tau expression from an equal ratio of 3R and 4R isoforms to primarily 3R isoforms. Both 3R and 4R isoforms of tau normally can enter the nucleus and bind to DNA but the misfolding of tau into NFTs prevents tau from entering the nucleus. Our lab has evidence that through DNA binding tau may repress the expression of the Nitric Oxide Synthase I (NOS1) gene by binding to a TG repeat sequence ((TG)(m)TA(TG)(n)) within the promoter region of the NOS1 gene. The enzyme, NOS1, is known to be misregulated in AD and when present in larger amounts is thought to contribute to neurodegeneration by producing excessive amounts of the free radical nitric oxide. The TG repeat that tau appears to bind to has varying sizes in different people, and having a shorter TG polymorphism has been linked to AD. To provide additional evidence that tau binds specifically to the TG repeat and learn more about the DNA binding capabilities of various tau isoforms, Electrophoretic Mobility Shift Assays, or EMSA’s were used to examine tau-DNA interactions. These experiments show that purified tau does bind to the TG repeat in the NOS1 promoter and that nuclear extracts from cells with and without tau have different TG repeat binding activities. The EMSA experiments also suggest that 4R isoforms of tau may have better DNA binding capabilities than 3R isoforms. Additional work needs to be done to confirm these studies and show if tau solely binds to the TG repeat of the NOS1 promoter. Overall, this research is the first to report tau might act as a transcription factor, increases understanding of tau’s binding actions, and may illuminate a deeper understanding of tau and its role in Alzheimer’s Disease.