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

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...

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Published in:Acta neuropathologica communications 2021-01, Vol.9 (1), p.15-15, Article 15
Main Authors: Ding, Xuebing, Xiang, Zhi, Qin, Chi, Chen, Yongkang, Tian, Haiyan, Meng, Lin, Xia, Danhao, Liu, Han, Song, Jia, Fu, Jun, Ma, Mingming, Wang, Xuejing
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Binding proteins
Brain
Genetic aspects
Genetic engineering
Medical research
Medicine, Experimental
Nervous system
Neurons
Pathology
Phenotype
Preformed fibrils
Prion-like transmission
Protein binding
Proteins
Pyramidal tract
Spinal cord
Transactive response DNA-binding protein 43 kDa
Transgenic animals
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Summary: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.
ISSN:2051-5960
2051-5960
DOI:10.1186/s40478-020-01112-3