Prion-like properties of pathological TDP-43 aggregates from diseased brains

Cell Rep. 2013 Jul 11;4(1):124-34. doi: 10.1016/j.celrep.2013.06.007. Epub 2013 Jul 3.


TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / metabolism*
  • Apoptosis
  • Brain / metabolism*
  • Cell Line, Tumor
  • Exosomes / metabolism
  • Frontotemporal Dementia / metabolism*
  • HEK293 Cells
  • Humans
  • Inclusion Bodies / metabolism*
  • Phosphorylation
  • Polymerization*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Denaturation
  • Proteolysis
  • Ubiquitination


  • Proteasome Endopeptidase Complex