Molecular and environmental drivers of tau post-translational modifications and tau pathology

Tau is an intrinsically disordered protein that functions to support cytoskeletal stability by binding microtubules in neuronal axons. While tau is involved in healthy neuronal function, it can become pathogenic by forming protein aggregates leading to neurologic diseases collectively known as tauopathies, which include Alzheimer's disease, frontotemporal dementia, and chronic traumatic encephalopathy. Post-translational modifications, including phosphorylation, glycosylation, acetylation, methylation, ubiquitination, and protein truncation are molecular drivers that promote tau aggregation and subsequent disease development. There is a growing, but incomplete, understanding of the complex crosstalk that occurs among distinct modifications and how they orchestrate tau pathogenesis in concert. The drivers of tau post-translational modifications are not fully understood, but environmental factors, such as traumatic brain injuries, microbial infections, alcohol abuse, chronic stress, and heavy metal pollutants, increase risk of tau pathology formation. In this article we review the current literature describing the molecular changes that increase tau aggregation propensity, the environmental factors that promote those changes, and the multifactorial crosstalk that modulates tau pathogenesis. Our goal is to outline the biological pathways and molecular factors that drive tau pathogenesis in order to identify potential points of behavioral and/or therapeutic intervention for tauopathies.