The tau protein is a key contributor to multiple neurodegenerative diseases. The pathology of tau is thought to be related to tau’s propensity to form self-templating fibrillar structures that allow tau fibers to propagate in the brain by prion-like mechanisms. Unresolved issues with respect to tau pathology are how the normal function of tau and its misregulation contribute to disease, how cofactors and cellular organelles influence the initiation and propagation of tau fibers, and determining the mechanism of tau toxicity. Herein, we review the connection between tau and degenerative diseases, the basis for tau fibrilization, and how that process interacts with cellular molecules and organelles. One emerging theme is that tau interacts with RNA and RNA-binding proteins, normally and in pathologic aggregates, which may provide insight into alterations in RNA regulation observed in disease.
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