Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice

Acta Neuropathol Commun. 2021 Jan 18;9(1):15. doi: 10.1186/s40478-020-01112-3.


Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. In this study, we reported that injection of TDP-43 preformed fibrils (PFFs) into the primary motor cortex (M1) of Thy1-e (IRES-TARDBP) 1 mice induced the spreading of pathological TDP-43 along pyramidal tract axons anterogradely. Moreover, TDP-43 PFFs-injected Thy1-e (IRES-TARDBP) 1 mice displayed ALS-like neuropathological features and symptoms, including motor dysfunctions and electrophysiological abnormalities. These findings provide direct evidence that transmission of pathological TDP-43 along pyramidal tract induces ALS-like phenotypes, which further suggest the potential mechanism for TDP-43 proteinopathy.

Keywords: Amyotrophic lateral sclerosis; Preformed fibrils; Prion-like transmission; Pyramidal tract; Transactive response DNA-binding protein 43 kDa.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Axonal Transport*
  • DNA-Binding Proteins / genetics*
  • Humans
  • Mice
  • Mice, Transgenic
  • Motor Cortex / metabolism*
  • Motor Cortex / pathology
  • Protein Aggregates*
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology
  • Protein Aggregation, Pathological / physiopathology
  • Pyramidal Tracts / metabolism*
  • Pyramidal Tracts / pathology


  • DNA-Binding Proteins
  • Protein Aggregates
  • TARDBP protein, human