Elsevier

Neuroscience Research

Volume 77, Issue 4, December 2013, Pages 234-241
Neuroscience Research

A unique mouse model for investigating the properties of amyotrophic lateral sclerosis-associated protein TDP-43, by in utero electroporation

https://doi.org/10.1016/j.neures.2013.09.009Get rights and content
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Highlights

  • We established new in vivo mouse model expressing ALS-associated proteins.

  • In utero electroporation was used for this model.

  • TDP-43 inclusions were observed in the motor area of the cortex in the mouse brains.

  • These inclusions were phosphorylated and ubiquitinated as human pathology of ALS.

  • This method can be used for other proteins in the neurodegenerative diseases.

Abstract

TDP-43 is a discriminative protein that is found as intracellular aggregations in the neurons of the cerebral cortex and spinal cord of patients with amyotrophic lateral sclerosis (ALS); however, the mechanisms of neuron loss and its relation to the aggregations are still unclear. In this study, we generated a useful model to produce TDP-43 aggregations in the motor cortex using in utero electroporation on mouse embryos. The plasmids used were full-length TDP-43 and C-terminal fragments of TDP-43 (wild-type or M337V mutant) tagged with GFP. For the full-length TDP-43, both wild-type and mutant, electroporated TDP-43 localized mostly in the nucleus, and though aggregations were detected in embryonic brains, they were very rarely observed at P7 and P21. In contrast, TDP-43 aggregations were generated in the brains electroporated with the C-terminal TDP-43 fragments as previously reported in in vitro experiments. TDP-43 protein was distributed diffusely—not only in the nucleus, but also in the cytoplasm—and the inclusion bodies were ubiquitinated and included phosphorylated TDP-43, which reflects the human pathology of ALS. This model using in utero electroporation of pathogenic genes into the brain of the mouse will likely become a useful model for studying ALS and also for evaluation of agents for therapeutic purpose, and may be applicable to other neurodegenerative diseases, as well.

Keywords

Amyotrophic lateral sclerosis
TDP-43
In utero electroporation
Inclusion body

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