Fig. 6

Model for the evolution of tau pathology a Stress elicits translocation of nuclear RBPs, such as TIA1 and HNRNPA0, to the cytoplasm where they distribute diffusely in the cytoplasm. b Core nucleating RBPs, such as TIA1, coalesce to form SGs, in a process that is stimulated by tau oligomers. Secondary nucleation brings in other RBPs, such as EWSR1, PABP, DDX6, EIFs, etc. c Persistent stress (such as occurs in disease) causes particularly insoluble RBPs (and tau) to consolidate to form persistent pathological stress granules. More soluble RBPs separate from the persistent pathological SG, and disperse without aggregating. d The tau oligomers evolve into fibrils forming pathological puncta, which contain classic markers of pathology such as hyper-phosphorylation and ubiquitination [43]. Other RBPs that remain associated with the persistent pathological SG, begin to form aggregated puncta around the tau puncta. e Tau fibrillizes forming neurofibrillary tangles, which are relatively inert, do not act in the translational stress response and contain few RBSs