期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 9, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40478-020-01112-3
关键词
Amyotrophic lateral sclerosis; Transactive response DNA-binding protein 43 kDa; Pyramidal tract; Preformed fibrils; Prion-like transmission
资金
- National Natural Science Foundation of China [81873791, 81671267, 81471307]
- Natural Science Foundation of Henan province [K2015-61X-22297-03-4, 2019-01551]
The research findings suggest that the transmission of pathological TDP-43 along the pyramidal tract induces ALS-like neuropathology and symptoms. This provides direct evidence for the potential mechanism of TDP-43 proteinopathy.
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.
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