Neurofibrillary tangles and granulovacuolar degeneration bodies: Examining protein aggregation and accumulationPublic Deposited
Neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) and tauopathies occurs when tau protein adopts secondary structure and self-aggregates within neurons. Accompanying NFT maturation are post-translational modifications to tau; hyperphosphorylation, truncation and conformational changes occur in a highly sequential manner. In contrast, granulovacuolar degeneration bodies (GVDs) are a second type of inclusion body that is found within neurons of the hippocampus alongside NFTs in AD and tauopathies. The composition of GVDs includes a number of proteins involved either in the post-translational modification of tau or related to the proteasome system of the cell. In this dissertation, we will examine the role of a protein kinase, stress-activated protein kinase/ c-Jun N-terminal kinase (SAPK/JNK) that is an important factor in tau phosphorylation and tau truncation by caspase. First, we will identify the granular structures that p-SAPK/JNK forms in relation to NFT formation and AD. Secondly, we will characterize these granules as GVD bodies. Finally, we will explore how inhibition of the proteasome can lead to creation of p-SAPK/JNK-positive granular structures in N2A cells as well as tau aggregates that undergo post-translational modifications reminiscent of NFT formation.