Background Neurodegenerative diseases with tau pathology, or tauopathies, include Alzheimer’s Disease and related dementia disorders. Previous work has shown that loss of the poly(A) RNA-binding protein gene sut2/MSUT2 strongly suppressed tauopathy in C. elegans, human cell culture, and mouse models of tauopathy. However, the mechanism of suppression is still unclear. Recent work has shown that MSUT2 protein interacts with the THO complex and ALYREF, which are components of the mRNA nuclear export complex. Additionally, previous work showed ALYREF homolog Ref1 modulates TDP-43 and G 4 C 2 toxicity in D. melanogaster models.
Methods We used transgenic C. elegans models of tau or TDP-43 toxicity to investigate the effects of loss of ALYREF function on tau and TDP-43 toxicity. In C. elegans, there are three genes that are homologous to human ALYREF: aly-1, aly-2, and aly-3.
Results We found that loss of C. elegans aly gene function, especially loss of both aly-2 and aly-3, suppressed tau-induced toxic phenotypes. Loss of aly-2 and aly-3 was also able to suppress TDP-43-induced behavioral deficits. However, loss of aly-2 and aly-3 had divergent effects on mRNA and protein levels as total tau protein levels were reduced while mRNA levels were increased, but no significant effects were seen on total TDP-43 protein or mRNA levels.
Conclusions Our results suggest that although aly genes modulate both tau and TDP-43-induced toxicity phenotypes, the molecular mechanisms of suppression are different and separated from impacts on mRNA and protein levels. Altogether this study highlights the importance of elucidating RNA-related mechanisms in both tau and TDP-43-induced toxicity.