The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging

Abstract

Highlights What are the main findings? Stress induces phase-separated biomolecular condensates (stress granules) that serve as nucleation sites for the aggregation of neurodegenerative disease-linked RNA-binding proteins. Stress-mediated phosphorylation stimulates tau oligomerization, which normally functions to stabilize stress granules. This process becomes pathologically amplified in disease, leading to excessive stress granule accumulation. What are the implications of the main findings? Reducing biomolecular condensates in stress and disease could provide a general effective therapeutic approach for multiple neurodegenerative diseases. Translational stress pathways, such as eIF2 and eIF3, are specific pathways being pursued for reducing levels of stress granules, aggregated RNA binding proteins and oligomeric Tau. Abstract RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer’s disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging.