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

• DOI: 10.1186/s40478-020-01112-3
• Publication Date: 2021-01-18T18:02:40Z
• Authors: Xuebing Ding; Zhi Xiang; Chi Qin; Yongkang Chen; Haiyan Tian; Lin Meng; Danhao Xia; Han Liu; Jia Song; Jun Fu; Mingming Ma; Xuejing Wang
• Keywords: 0303 health sciences; Research; Amyotrophic Lateral Sclerosis; Transactive response DNA-binding protein 43 kDa; Motor Cortex; Pyramidal Tracts; Mice, Transgenic; Preformed fibrils; Amyotrophic lateral sclerosis; Axonal Transport; Protein Aggregation, Pathological; 3. Good health; DNA-Binding Proteins; Mice; Protein Aggregates; 03 medical and health sciences; Animals; Humans; Pyramidal tract; Neurology. Diseases of the nervous system; Prion-like transmission; RC346-429

AbstractTransactive 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.