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

Xuebing Ding,Danhao Xia,Xuejing Wang,Zhi Xiang,Jia Song,Haiyan Tian,Han Liu,Yongkang Chen,Jun Fu,Mingming Ma,Lin Meng,Chi Qin

doi:10.1186/s40478-020-01112-3

Abstract

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal progressive degenerative motor neuron disorder with unknown etiology [4, 37, 41]
Anterograde transsynaptic spread of pathological TDP‐43 along pyramidal tract after intra‐primary motor cortex injection of TDP‐43 preformed fibrils (PFFs) We first examined the structure and morphology of transactive response DNA-binding protein 43 kDa (TDP-43) PFFs using a transmission electron microscope (TEM), fluorescence spectroscopy with thioflavin T (ThT), and proteinase K (PK) resistance analysis
Even in the absence of agitation, the addition of 10% amounts of TDP-43 PFFs was sufficient to trigger the fibrillation of soluble TDP-43 monomers, which was confirmed by the increase in the ThT fluorescence intensity (Fig. 1f )

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal progressive degenerative motor neuron disorder with unknown etiology [4, 37, 41]. Cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43) inclusion was identified as a pathological hallmark of patients with ALS [2, 25, 33]. Accumulating clinical and experimental evidence suggests that ALS displays considerable properties similar to the prion diseases, with misfolded TDP-43 acting as a “prion-like” protein [39]. TDP-43 has been identified as an intrinsically aggregation-prone protein whose C-terminal domain is critical for spontaneous aggregation [13, 39]. In 2018, Svahn and his colleagues first demonstrated the nucleo-cytoplasmic transport of TDP-43 using a zebrafish model [40]. No animal model has been established to test whether the spreading of TDP-43 pathology could induce the pathological changes and clinical phenotypes of ALS

Methods

Results

Conclusion