Abstract
The development of insoluble, intracellular neurofibrillary tangles composed of the microtubule-associated protein tau is a defining feature of tauopathies, including Alzheimer’s disease (AD). Accumulating evidence suggests that tau pathology co-localizes with RNA binding proteins (RBPs) that are known markers for stress granules (SGs). Here we used proteomics to determine how the network of tau binding proteins changes with disease in the rTg4510 mouse, and then followed up with immunohistochemistry to identify RNA binding proteins that co-localize with tau pathology. The tau interactome networks revealed striking disease-related changes in interactions between tau and a multiple RBPs, and biochemical fractionation studies demonstrated that many of these proteins including hnRNPA0, EWSR1, PABP and RPL7 form insoluble aggregates as tau pathology develops. Immunohistochemical analysis of mouse and human brain tissues suggest a model of evolving pathological interaction, in which RBPs co-localize with pathological phospho-tau but occur adjacent to larger pathological tau inclusions. We suggest a model in which tau initially interacts with RBPs in small complexes, but evolves into isolated aggregated inclusions as tau pathology matures.
Highlights
RNA binding proteins (RBPs) have emerged as major factors in a number of neurodegenerative disorders, including tauopathies [31, 32]
A smaller number of RBPs increase the association of tau with disease, including EWSR1, TAF15 and hnRNPA0, each of which have been linked to amyotrophic lateral sclerosis (ALS) (e.g., EWSR1 or TAF15) or have related family members linked to ALS
For the RBPs examined in this manuscript, T-cell intracellular antigen 1 (TIA1) showed the strongest co-localization with tau pathology
Summary
RNA binding proteins (RBPs) have emerged as major factors in a number of neurodegenerative disorders, including tauopathies [31, 32]. Other RBPs have been implicated in AD, Huntington’s disease, and Creutzfeldt-Jakob disease [24] Following these initial discoveries, evidence suggests that transient aggregation mediated by low-complexity domains within RBPs is crucial for the involvement of these proteins in disease. RBPs typically contain a “prion-like”, low complexity glycine-rich domain in their sequences, which regulate their self-aggregation [21, 35]. This regulated aggregation is important for RBP function, as many RBPs regulate the formation of a variety of ribonucleoprotein (RNP) granules. Many disease-linked RBPs are proteins involved in the formation and maintenance of SGs
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