Journal
ACTA NEUROPATHOLOGICA COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s40478-018-0574-5
Keywords
Alzheimer's disease; Neurofibrillary tangle; Immunohistochemistry; Mass spectrometry; Protein interactome; Protein aggregation
Categories
Funding
- NIH [AG050471, NS089544, ES020395, AG056318, NS091329, AG028383, MD009205]
- BrightFocus Foundation
- Alzheimer Association
- Cure Alzheimer's Fund
- Thome Medical Foundation [NS106751]
- Alzheimer's Association [NIRG-14-322441]
- Department of Defense [AZ140097]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008541] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS091329, F31NS106751, R01NS089544] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG050471, RF1AG056318, P30AG028383, RF1AG061706] Funding Source: NIH RePORTER
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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.
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