The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology

Abstract

Fragments of the TAR DNA-binding protein-43 (TDP43) are major components of intracellular aggregates associated with amyotrophic lateral sclerosis and frontotemporal dementia. A variety of C-terminal fragments (CTFs) exists with distinct N-termini; however, little is known regarding their differences in metabolism and aggregation dynamics. Previously, we found that specific CTFs accumulate in the absence of the Arg/N-end rule pathway of the ubiquitin proteasome system (UPS) and that their degradation requires Arginyl-tRNA-protein transferase 1 (ATE1). Here, we examined two specific CTFs of TDP43 (TDP43 219 and TDP43 247) which are ∼85% identical and differ at their N-terminus by 28 amino acids. We found that TDP43 247 is degraded primarily by the Arg/N-end rule pathway, whereas degradation of TDP43 219 continues in the absence of ATE1. These fragments also differ in aggregation propensity and form morphologically distinct aggregates. This work reveals that the N-terminus of otherwise similar CTFs has profound effects on fragment behavior and may influence clinical outcomes in neurodegeneration associated with aggregation.