Short-term suppression of A315T mutant human TDP-43 expression improves functional deficits in a novel inducible transgenic mouse model of FTLD-TDP and ALS

Abstract

The nuclear transactive response DNA-binding protein 43 (TDP-43) undergoes relocalization to the cytoplasm with formation of cytoplasmic deposits in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Pathogenic mutations in the TDP-43-encoding TARDBP gene in familial ALS as well as non-mutant human TDP-43 have been utilized to model FTD/ALS in cell culture and animals, including mice. Here, we report novel A315T mutant TDP-43 transgenic mice, iTDP-43(A315T), with controlled neuronal over-expression. Constitutive expression of human TDP-43(A315T) resulted in pronounced early-onset and progressive neurodegeneration, which was associated with compromised motor performance, spatial memory and disinhibition. Muscle atrophy resulted in reduced grip strength. Cortical degeneration presented with pronounced astrocyte activation. Using differential protein extraction from iTDP-43(A315T) brains, we found cytoplasmic localization, fragmentation, phosphorylation and ubiquitination and insolubility of TDP-43. Surprisingly, suppression of human TDP-43(A315T) expression in mice with overt neurodegeneration for only 1 week was sufficient to significantly improve motor and behavioral deficits, and reduce astrogliosis. Our data suggest that functional deficits in iTDP-43(A315T) mice are at least in part a direct and transient effect of the presence of TDP-43(A315T). Furthermore, it illustrates the compensatory capacity of compromised neurons once transgenic TDP-43 is removed, with implications for future treatments.

Early Cognitive/Social Deficits and Late Motor Phenotype in Conditional Wild-Type TDP-43 Transgenic Mice

“…These data argues against an unspecific effect on non-motor behaviors due to increased anxiety or impaired visual function. Additionally, they suggest that TDP-43-WT mice may show disinhibition, as reported in other mouse models for FTD (Yin et al, 2010; Ke et al, 2015; Przybyla et al, 2016). …”

Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons

“…These studies collectively suggest that TDP-43 is a highly aggregation-prone protein [27] and that a variety of molecular pathways can lead to cytoplasmic mislocalisation, aggregation and inclusion formation [14, 20, 30, 56, 71]. Moreover, although a true phenocopy of ALS/FTLD has been elusive in TDP-43 animal models [26], the overexpression of mutant forms of TDP-43 in mice does result in the development of motor impairment and lethality [29, 58, 63]. A key challenge with these animal models is that similar to the clinical postmortem situation, the disease histopathology only provides snapshots at different time points during disease progression.…”

Prion‐like propagation as a pathogenic principle in frontotemporal dementia

“…Similar results were obtained in a study using an inducible TDP‐43 transgene with a point mutation where suppression of transgene expression in mice with overt neurodegeneration for only 1 week was sufficient to clear pathological TDP‐43 and to significantly improve motor and behavioral deficits (Ke et al . ). This suggests that the presence of intracellular pathological TDP‐43 at a certain point might not be sufficient for cell‐to‐cell spread and propagation of disease pathology without a continuous pool of cytoplasmic TDP‐43.…”