Aberrant dynein function promotes TDP-43 aggregation and upregulation of p62 in male mice harboring transgenic human TDP-43

Abstract

Objective

Most TDP-43 mouse models of ALS do not display cytoplasmic mislocalisation or protein aggregation of TDP-43 in spinal motor neurons in vivo. Thus, we investigated whether a combination of defective dynein with a TDP-43 mutation could trigger TDP-43 pathology.

Methods

Using immunohistochemical methods we examined the intracellular motor neuron pathology of the offspring of TDP-43^WT and TDP-43^M337V transgenic mice bred to heterozygous Loa mice, which carry an autosomal dominant mutation in dynein cytoplasmic 1 heavy chain 1 (Dync1h1).

Results

These mice did not exhibit TDP-43 mislocalisation in spinal motor neurons, but the expression of mutant dynein in combination with wildtype human TDP-43 resulted in p62 upregulation and TDP-43 aggregation, thus partially recapitulating the human disease.

Conclusions

These findings provide new insights into the possible relationship between dynein and TDP-43 and could prove useful in future studies looking to elucidate the mechanism behind the TDP-43 pathology observed in ALS.

Keywords:

• Amyotrophic lateral sclerosis
• ALS
• TDP-43
• dynein
• motor neuron disease

Acknowledgements

We would like to thank Dr Greig Joilin for critically reviewing the first draft of the manuscript.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Data availability statement

The data that support the findings of this study are available from the corresponding author, MH, upon reasonable request.

Additional information

Funding

This work was supported by the Sussex Neuroscience PhD Programme (EC), the Motor Neurone Disease Association project grant Dupuis-Hafezparast/Apr16/852-791 (FAS), and the Motor Neurone Disease Association project grant Talbot/Mar10/6063. Part of the consumables for this project was supported by an alumni donation fund from Marion Brownridge.