Presentation 3: Translational dysregulation promotes pathogenic events in tauopathies

Background A major challenge in the field of tau‐associated neurodegeneration is the identification of the pathogenic mechanisms leading to disease. Tau is best known for associating and stabilizing microtubules; however, emerging results identifying alternate tau functions opens a new opportunity to understand the molecular basis of disease. Given the association of tau with ribosomes and RNA, and the enhancement of this interaction in Alzheimer’s disease, we hypothesized that the aberrant tau‐ribosome interaction impairs (increases and decreases) transcripts that are necessary for cellular homeostasis. For nearly thirty years, the consequences of tau‐ribosome complexes were unknown until now. Methods We used in vitro models such as GFP‐based cell‐free translation assays and surface sensing of translation (SUnSET) assays in immortalized and primary neuronal cultures. Moreover, we pioneered in vivo SUnSET in the brains of tau transgenic mice, and coupled these techniques with proteomics. We validated our results using human brain samples from AD and non‐demented controls. Finally, we performed ribosomal profiling assays using in vitro models of tauopathy. Results We demonstrate that pathological tau species associate robustly with ribosomes profoundly shifting the translatome. Surprisingly, a significant number of proteins whose translation was impaired corresponded to ribosomal proteins. We also identified that the ribosomal protein S6, which regulates translation of the machinery necessary for translation (ribosomal proteins as well as elongation and initiation factors), was significantly reduced in vitro, in vivo, and in human brains. Finally, we also found major shifts in the integrity of AD brain polysomes as a consequence of tau aggregation. Conclusion Pathological tau species negatively regulate ribosomal specificity thereby shifting the translatome.