Elsevier

Neurobiology of Aging

Volume 35, Issue 1, January 2014, Pages 79-87
Neurobiology of Aging

Regular article
Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice

https://doi.org/10.1016/j.neurobiolaging.2013.07.006Get rights and content

Abstract

Accumulation of the transactive response DNA-binding protein 43 (TDP-43) is a major hallmark of several neurodegenerative disorders, collectively known as TDP-43 proteinopathies. The most common TDP-43 proteinopathies, frontotemporal lobar degeneration with TDP–43-positive inclusions, and amyotrophic lateral sclerosis, share overlapping neuropathological and clinical phenotypes. The development and detailed analysis of animal models of TDP-43 proteinopathies are critical for understanding the pathogenesis of these disorders. Transgenic mice overexpressing mutant human TDP-43 (herein referred to as hTDP-43) are characterized by neurodegeneration and reduced life span. However, little is known about the behavioral phenotype of these mice. Here we report the novel finding that hTDP-43 mice develop deficits in cognition, motor performance, and coordination. We show that these behavioral deficits are associated with the accumulation of nuclear and cytosolic TDP-43 C-terminal fragments, a decrease in endogenous TDP-43 levels, and synaptic loss. Our findings provide critical insights into disease pathology, and will help guide future preclinical studies aimed at testing the effects of potential therapeutic agents on the onset and progression of TDP-43 proteinopathies.

Introduction

Transactive response DNA-binding protein 43 (TDP-43) is an ubiquitously expressed RNA- and DNA-binding protein. Physiologically, TDP-43 is involved in RNA transport and stabilization, and DNA silencing (Buratti and Baralle, 2008). In pathological states, TDP-43 accumulation leads to a spectrum of diseases known as TDP-43 proteinopathies (Chen-Plotkin et al., 2010), which include amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP–43-positive inclusions (FTLD-TDP). Mutations in the C-terminal glycine-rich domain of TDP-43 cause ALS with TDP-43 accumulation (Pesiridis et al., 2009). In comparison, TDP-43 accumulation triggered by loss-of-function mutations in the progranulin gene leads to FTLD-TDP (Baker et al., 2006).

TDP-43 primarily resides in the nucleus; however, in TDP-43 proteinopathies, it mislocalizes to the cytoplasm, where it accumulates and forms intracellular inclusions (Neumann et al., 2006). A hallmark of TDP-43 proteinopathies is the accumulation of TDP-43 C-terminal fragments, mainly of 35 and 25 kDa, herein referred to as TDP-35 and TDP-25, respectively (Neumann et al., 2006). Notably, transgenic mice overexpressing TDP-25 develop cognitive deficits that are associated with the buildup of TDP-25 and mislocalization of TDP-43, further suggesting a primary role for TDP-25 in the pathogenesis of this disorder (Caccamo et al., 2012). Other morbidities associated with TDP-43 proteinopathies include neuroinflammation, accumulation of ubiquitin-positive inclusions, and neurodegeneration (Neumann, 2009). The two major TDP-43 proteinopathies, ALS and FTLD-TDP, share common neuropathological features such as TDP-43 accumulation and mislocalization, inflammation, and neurodegeneration (Chen-Plotkin et al., 2010).

Several animal models of TDP-43 proteinopathies have been developed by overexpressing wild type or mutant human TDP-43 under the control of various promoters (Tsao et al., 2012). When the TDP-43 transgene is widely expressed throughout the brain and spinal cord using the murine prion promoter, mice quickly develop a motor phenotype that culminates with paralysis and premature death (Stallings et al., 2010, Wegorzewska et al., 2009, Xu et al., 2010, Xu et al., 2011). Similar results have been obtained using more selective promoters (Shan et al., 2010, Swarup et al., 2011, Tsai et al., 2010, Wils et al., 2010, Zhou et al., 2010). One of the earliest animal models (herein referred to as hTDP-43) was generated by overexpressing the human TDP-43 cDNA harboring the A315T mutation under the control of the prion promoter (Wegorzewska et al., 2009). This mutation segregates with all affected members of an autosomal dominant motor neuron disease (Gitcho et al., 2008); however, it remains to be established whether the mutant TDP-43 leads to neurodegeneration via a gain- or a loss-of-function mutation. The hTDP-43 mice develop age-dependent neurodegeneration associated with motor dysfunction and central nervous system pathology (Wegorzewska et al., 2009). Despite the large number of animal models of TDP-43 proteinopathies, the effect of mutant human TDP-43 on cognitive function remains elusive. To address this issue, we used the hTDP-43 mice, which develop age-dependent neurodegeneration associated with the accumulation of ubiquitinated proteins in cortex and spinal cord, mimicking several features of TDP-43 proteinopathies (Wegorzewska et al., 2009). However, whether these mice develop cognitive deficits reminiscent of those developed by FTLD-TDP and ALS patients remains unknown.

Section snippets

Mice

The hTDP-43 mice were obtained from the Jackson laboratories (stock number: 010700) and a colony was established in our laboratory by breeding hTDP-43 hemizygous female mice with wild type C57BL/6J male mice. Generation of mice was described by (Wegorzewska et al., 2009). Briefly, the human cDNA encoding mutant TDP-43 (A315T) was placed under the control of the prion promoter and used for microinjections. The cDNA contained a flag-tag at the N-terminus. Only female hTDP-43 mice were used in

Results

The two major TDP-43 proteinopathies, ALS and FTLD-TDP, are characterized by motor and cognitive dysfunction. To determine whether expression of human mutant TDP-43 impairs cognition, we tested 6-month-old hTDP-43 female mice in a battery of cognitive tests dependent on different brain regions. A previous report using these mice indicated that they develop gait abnormalities at 3–4 months of age and become paralyzed shortly thereafter (Wegorzewska et al., 2009). In our colony, which was

Discussion

ALS and FTLD-TDP share overlapping clinical and pathological phenotypes, suggestive of common pathogenic mechanisms (Baloh, 2011, Mukherjee et al., 2006). Toward this end, both disorders are characterized by the accumulation of TDP-43, which identification has greatly enhanced the pace of discovery toward understanding the pathogenesis of these disorders (Neumann et al., 2006). Despite this wealth of knowledge, there are no current cures or treatments for these disorders.

Animal models represent

Disclosure statement

The authors have no conflicts of interest. No human subjects were used in this study.

Acknowledgements

David X. Medina is supported by an individual pre-doctoral award 1 F31 NS079120-01A1. Miranda E. Orr is supported by a training grant from the NIA (T32 AG021890).

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