Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction

Abstract

Ubiquitin-immunoreactive neuronal inclusions composed of TAR DNA binding protein of 43 kDa (TDP-43) are a major pathological feature of frontotemporal lobar degeneration (FTLD-TDP). In vivo studies with TDP-43 knockout mice have suggested that TDP-43 plays a critical, although undefined role in development. In the current report, we generated transgenic mice that conditionally express wild-type human TDP-43 (hTDP-43) in the forebrain and established a paradigm to examine the sensitivity of neurons to TDP-43 overexpression at different developmental stages. Continuous TDP-43 expression during early neuronal development produced a complex phenotype, including aggregation of phospho-TDP-43, increased ubiquitin immunoreactivity, mitochondrial abnormalities, neurodegeneration and early lethality. In contrast, later induction of hTDP-43 in the forebrain of weaned mice prevented early death and mitochondrial abnormalities while yielding salient features of FTLD-TDP, including progressive neurodegeneration and ubiquitinated, phospho-TDP-43 neuronal cytoplasmic inclusions. These results suggest that neurons in the developing forebrain are extremely sensitive to TDP-43 overexpression and that timing of TDP-43 overexpression in transgenic mice must be considered when distinguishing normal roles of TDP-43, particularly as they relate to development, from its pathogenic role in FTLD-TDP and other TDP-43 proteinopathies. Finally, our adult induction of hTDP-43 strategy provides a mouse model that develops critical pathological features that are directly relevant for human TDP-43 proteinopathies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-012-0979-3) contains supplementary material, which is available to authorized users.

Studies of alternative isoforms provide insight into TDP-43 autoregulation and pathogenesis

“…3B). Given in vitro results may not faithfully model in vivo systems, we sought to confirm these findings by assaying the abundance of Tardbp transcripts in the cortex of two transgenic mouse lines that overexpress human wild type or mutant M337V TDP-43 (Cannon et al 2012;D'Alton et al 2014). With the exception of junction 1, we observed increased expression of 6D junctions in 2-mo-old transgenic animals relative to nontransgenics (Fig.…”

Mitochondrial Dysfunction and Decrease in Body Weight of a Transgenic Knock-in Mouse Model for TDP-43

“…Mitochondrial abnormalities were also reported from a mouse model that overexpressed human wild type TDP-43 in the developing forebrain conditionally. However, they were not observed after delayed overexpression in adult animals and were therefore considered developmental abnormalities (96). Whether mitochondrial abnormality could explain the observed metabolic changes and altered body weight composition of hTDP-43 A315T animals will be subject of future studies.…”

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

“…Transgenic lines include constitutive expression of non-mutant and mutant TDP-43 under control of different promoters [45,46], as well as the usage of inducible promoter systems [5,8,21]. Both approaches reproduced some neuropathological features of FTLD-TDP and ALS, and mice with inducible TDP-43 expression showed significant neuronal cell loss.…”

“…Both approaches reproduced some neuropathological features of FTLD-TDP and ALS, and mice with inducible TDP-43 expression showed significant neuronal cell loss. While neuropathological changes have been examined in the latter models [5,8,21], the number of functional studies is low [24].…”