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

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.