Transgenic Dendra2::tau expression allows in vivo monitoring of tau proteostasis in C. elegans.

Protein homeostasis is perturbed in aging-related neurodegenerative diseases called tauopathies, which are pathologically characterized by aggregation of the microtubule-associated protein tau. Transgenic Caenorhabditis elegans serve as a powerful model organism to study tauopathy disease mechanisms, but moderating transgenic expression level has proven problematic. To study neuronal tau proteostasis, we generated a suite of transgenic strains expressing low, medium, or high levels of Dendra2::tau fusion proteins by comparing integrated multicopy transgene arrays with single-copy safe-harbor locus strains generated by recombinase-mediated cassette exchange. Multicopy Dendra2::tau strains exhibit expression level-dependent neuronal dysfunction that is modifiable by known genetic suppressors or an enhancer of tauopathy. Single-copy Dendra2::tau strains lack distinguishable phenotypes on their own but enable detection of enhancer-driven neuronal dysfunction. We have employed multicopy Dendra2::tau strains in optical pulse-chase experiments measuring tau turnover in vivo and found Dendra2::tau turns over faster than the relatively stable Dendra2. Further, Dendra2::tau turnover is dependent on protein expression level and independent of TDP-43 co-expression. We present Dendra2::tau transgenic C. elegans as a novel tool for investigating molecular mechanisms of tau proteostasis.