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

Eleni Christoforidou; Fabio A Simoes; David Gordon; Kevin Talbot; Majid Hafezparast

doi:10.1080/21678421.2023.2239276

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

Amyotroph Lateral Scler Frontotemporal Degener. 2023 Jul 27:1-10. doi: 10.1080/21678421.2023.2239276. Online ahead of print.

Authors

Eleni Christoforidou¹, Fabio A Simoes¹, David Gordon², Kevin Talbot², Majid Hafezparast¹

Affiliations

¹ Department of Neuroscience, School of Life Sciences, University of Sussex, Brighton, UK and.
² Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

PMID: 37498094
DOI: 10.1080/21678421.2023.2239276

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: ALS; Amyotrophic lateral sclerosis; TDP-43; dynein; motor neuron disease.