The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction Journal Article


Authors: Inda, M. C.; Joshi, S.; Wang, T.; Bolaender, A.; Gandu, S.; Koren, J. 3rd; Che, A. Y.; Taldone, T.; Yan, P.; Sun, W.; Uddin, M.; Panchal, P.; Riolo, M.; Shah, S.; Barlas, A.; Xu, K.; Chan, L. Y. L.; Gruzinova, A.; Kishinevsky, S.; Studer, L.; Fossati, V.; Noggle, S. A.; White, J. R.; de Stanchina, E.; Sequeira, S.; Anthoney, K. H.; Steele, J. W.; Manova-Todorova, K.; Patil, S.; Dunphy, M. P.; Pillarsetty, N.; Pereira, A. C.; Erdjument-Bromage, H.; Neubert, T. A.; Rodina, A.; Ginsberg, S. D.; De Marco Garcia, N.; Luo, W.; Chiosis, G.
Article Title: The epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction
Abstract: Optimal functioning of neuronal networks is critical to the complex cognitive processes of memory and executive function that deteriorate in Alzheimer’s disease (AD). Here we use cellular and animal models as well as human biospecimens to show that AD-related stressors mediate global disturbances in dynamic intra- and inter-neuronal networks through pathologic rewiring of the chaperome system into epichaperomes. These structures provide the backbone upon which proteome-wide connectivity, and in turn, protein networks become disturbed and ultimately dysfunctional. We introduce the term protein connectivity-based dysfunction (PCBD) to define this mechanism. Among most sensitive to PCBD are pathways with key roles in synaptic plasticity. We show at cellular and target organ levels that network connectivity and functional imbalances revert to normal levels upon epichaperome inhibition. In conclusion, we provide proof-of-principle to propose AD is a PCBDopathy, a disease of proteome-wide connectivity defects mediated by maladaptive epichaperomes. © 2020, The Author(s).
Keywords: immunohistochemistry; signal transduction; controlled study; human tissue; protein expression; protein phosphorylation; unclassified drug; human cell; nonhuman; mouse; animal tissue; gene overexpression; image analysis; protein protein interaction; animal experiment; animal model; protein; cohort analysis; fluorescence polarization; proteomics; animalia; genetic transfection; brain; mammalian target of rapamycin; nerve cell plasticity; western blotting; heat shock protein 90; cognitive defect; heat shock protein 27; radioisotope; memory disorder; memory; toxicity; bioinformatics; beta catenin; medicine; mental health; alzheimer disease; polyacrylamide gel electrophoresis; tau protein; chaperone; hippocampus; pharmacokinetic parameters; beta actin; animal behavior; liquid chromatography-mass spectrometry; functional connectivity; radioimmunoprecipitation; brain toxicity; heat shock protein 110; brain electrophysiology; disease incidence; open field test; chaperonin 60; human; male; female; article; brain dysfunction; live cell imaging; epichaperome; heat shock cognate protein 70; iodine 131 pu ad; barnes maze test; protein connectivity based dysfunction
Journal Title: Nature Communications
Volume: 11
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2020-01-16
Start Page: 319
Language: English
DOI: 10.1038/s41467-019-14082-5
PUBMED: 31949159
PROVIDER: scopus
PMCID: PMC6965647
DOI/URL:
Notes: Article -- Export Date: 3 February 2020 -- Source: Scopus
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