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

Original publication

DOI

10.1080/21678421.2023.2239276

Type

Journal article

Journal

Amyotrophic lateral sclerosis & frontotemporal degeneration

Publication Date

07/2023

Pages

1 - 10

Addresses

Department of Neuroscience, School of Life Sciences, University of Sussex, Brighton, UK and.