Modified tau leads to neuronal and global ribosome dysfunction in C. elegans model of tauopathy

Abstract

Alzheimers disease (AD) is a neurodegenerative disease characterized by an early loss of memory formation which requires protein synthesis. Tau is an intrinsically disordered protein and is subject to extensive post-translational modifications (PTMs). Some PTMs have been shown to alter localization of tau and allow tau to disrupt protein translation. Protein interactome studies indicate that tau might interact with ribosomal proteins. Therefore, we hypothesized that tau is causing ribosomal dysfunction as an early event and this interaction is dependent on taus PTMs. To test this, we used a C. elegans strain expressing single copy insertion of human tau as well as two of the most frequent modified versions of tau in mechanosensory neurons. With our assay to measure translation, we showed that in our T231 phosphorylation mimetic strain, there was a significant decrease in neuronal translation. This mimetic strain also showed a significant decrease in median lifespan and locomotion. Unexpectedly, in all our Tau-expressing strains, we detected a significant decrease in whole worm translation, suggesting a possible role of tau to influence translation in other tissues in worm. Our in vitro, in vivo and ex vivo efforts to demonstrate tau-ribosome association via fluorescent polysome profiling have shown that there is no direct association between tau and the ribosome. Ribosome dysfunction caused by modified tau could be an early event in AD pathology before the pathological hallmarks appear.