The N Termini of TAR DNA-Binding Protein 43 (TDP43) C-Terminal Fragments Influence Degradation, Aggregation Propensity, and Morphology.
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) exist, 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 (TDP43219 and TDP43247), which are ∼85% identical and differ at their N termini by 28 amino acids. We found that TDP43247 is degraded primarily by the Arg/N-end rule pathway, whereas degradation of TDP43219 continues in the absence of ATE1. These fragments also differ in their aggregation propensities and form morphologically distinct aggregates. This work reveals that the N termini of otherwise similar CTFs have profound effects on fragment behavior and may influence clinical outcomes in neurodegeneration associated with aggregation.
['Kasu|Yasar Arfat T|YAT|', 'Alemu|Samrawit|S|', 'Lamari|Angela|A|', 'Loew|Nicole|N|', 'Brower|Christopher S|CS|']
D000595:Amino Acid Sequence D019881:Aminoacyltransferases D000690:Amyotrophic Lateral Sclerosis D000818:Animals D002460:Cell Line D004268:DNA-Binding Proteins D057809:HEK293 Cells D006801:Humans D051379:Mice D010446:Peptide Fragments D046988:Proteasome Endopeptidase Complex D066329:Protein Aggregates D066263:Protein Aggregation, Pathological D059748:Proteolysis D011994:Recombinant Proteins
TAR DNA-binding protein aggregation amyotrophic lateral sclerosis proteasome autophagy