TAU ASSOCIATES WITH RIBOSOMAL PROTEINS SHIFTING THE TRANSLATOME

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in vivoand in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. We performed microarrays and puromycin-based proteomics to measure changes in protein synthesis using rTg4510 tau transgenic mice. We corroborated these results using an in vitro cell culture model of inducible tau expression and human Alzheimer's brains at increasing stages of disease. Finally, we investigated the role of the ribosomal protein S6, which is a regulator of translation, using standard western blots and RT-PCR in human Alzheimer's brains. We determined that tau expression differentially shifts the transcriptome and the proteome and that the synthesis of ribosomal proteins is reversibly dependent on tau levels. We further extended these results to human brains and show that tau pathologically interacts with ribosomal protein S6 (rpS6 or S6), a crucial regulator of translation. Consequently, protein synthesis of transcripts under translational control by rpS6 were reduced under tauopathic conditions in Alzheimer's disease brains. Our data establish tau as a driver of RNA translation selectivity. Moreover, considering that regulation of protein synthesis is critical to learning and memory, aberrant tau-ribosome interactions in disease could explain the linkage between virtually every tauopathy and cognitive impairment and memory decline.