Overexpression of ALS-Associated p.M337V Human TDP-43 in Mice Worsens Disease Features Compared to Wild-type Human TDP-43 Mice

Jonathan Janssens,Ivy Cuijt,Gernot Kleinberger,Hans Wils,Geert Joris,Chantal Ceuterick-De Groote,Christine Van Broeckhoven,Samir Kumar-Singh

doi:10.1007/s12035-013-8427-5

Abstract

Mutations in TAR DNA-binding protein 43 (TDP-43) are associated with familial forms of amyotrophic lateral sclerosis (ALS), while wild-type TDP-43 is a pathological hallmark of patients with sporadic ALS and frontotemporal lobar degeneration (FTLD). Various in vitro and in vivo studies have also demonstrated toxicity of both mutant and wild-type TDP-43 to neuronal cells. To study the potential additional toxicity incurred by mutant TDP-43 in vivo, we generated mutant human TDP-43 (p.M337V) transgenic mouse lines driven by the Thy-1.2 promoter (Mt-TAR) and compared them in the same experimental setting to the disease phenotype observed in wild-type TDP-43 transgenic lines (Wt-TAR) expressing comparable TDP-43 levels. Overexpression of mutant TDP-43 leads to a worsened dose-dependent disease phenotype in terms of motor dysfunction, neurodegeneration, gliosis, and development of ubiquitin and phosphorylated TDP-43 pathology. Furthermore, we show that cellular aggregate formation or accumulation of TDP-43 C-terminal fragments (CTFs) are not primarily responsible for development of the observed disease phenotype in both mutant and wild-type TDP-43 mice.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-013-8427-5) contains supplementary material, which is available to authorized users.

Highlights

TAR DNA-binding protein 43 (TDP-43) is the major pathological inclusion protein involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) linked to TDP-43 pathology (FTLD-TDP), providing a molecular link that put these disorders in a common ALS-FTLD disease spectrum [1,2,3]
We previously demonstrated that overexpression of wildtype human TDP-43 under control of a neuronal murine Thy-1.2 promoter leads to a dose-dependent ALS-FTLDlike motor phenotype in two independent mouse lines (TAR4/4 and TAR6/6; hereafter called Wt-TAR4/4 and Wt-TAR6/6) [24]
Because TDP-43 aggregates are majorly present in neurons, the use of a neuronal Thy-1.2 promoter was preferred for these experiments as it drives expression preferentially in neurons

Summary

Introduction

TAR DNA-binding protein 43 (TDP-43) is the major pathological inclusion protein involved in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) linked to TDP-43 pathology (FTLD-TDP), providing a molecular link that put these disorders in a common ALS-FTLD disease spectrum [1,2,3]. ALS is the most common adult-onset form of motor neuron. Several functions of TDP-43 have been described such as a role in transcription, RNA splicing, microRNA biogenesis and development [10]. Comprehensive studies aimed at identifying RNA-binding targets for TDP-43 found a multitude of target RNAs including transcripts of genes involved in RNA metabolism, synaptic function, and central nervous system (CNS) development [11]. It remains unclear which of these functions, if any, are hampered by aberrant TDP-43 and trigger disease development [12]

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Results

Conclusion