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

Mol Cell Biol. 2018 Sep 14;38(19):e00243-18. doi: 10.1128/MCB.00243-18. Print 2018 Oct 1.


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.

Keywords: TAR DNA-binding protein; aggregation; amyotrophic lateral sclerosis; autophagy; proteasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Aminoacyltransferases / deficiency
  • Aminoacyltransferases / genetics
  • Aminoacyltransferases / metabolism
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Cell Line
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Mice
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Aggregates
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology
  • Proteolysis
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism


  • DNA-Binding Proteins
  • Peptide Fragments
  • Protein Aggregates
  • Recombinant Proteins
  • TARDBP protein, human
  • Aminoacyltransferases
  • Ate1 protein, mouse
  • Proteasome Endopeptidase Complex