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

TitleThe epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction.
Publication TypeJournal Article
Year of Publication2020
AuthorsInda MCarmen, Joshi S, Wang T, Bolaender A, Gandu S, Iii JKoren, Che AYue, Taldone T, Yan P, Sun W, Uddin M, Panchal P, Riolo M, Shah S, Barlas A, Xu K, Chan LYin L, Gruzinova A, Kishinevsky S, Studer L, Fossati V, Noggle SA, White JR, de Stanchina E, Sequeira S, Anthoney KH, Steele JW, Manova-Todorova K, Patil S, Dunphy MP, Pillarsetty NVK, Pereira AC, Erdjument-Bromage H, Neubert TA, Rodina A, Ginsberg SD, Garcia NDe Marco, Luo W, Chiosis G
JournalNat Commun
Volume11
Issue1
Pagination319
Date Published2020 01 16
ISSN2041-1723
KeywordsAlzheimer Disease, Animals, Brain, Brain Mapping, Cognitive Dysfunction, Executive Function, Female, Hippocampus, Humans, Male, Memory, Mice, Neural Pathways, Neuronal Plasticity, Proteome
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.

DOI10.1038/s41467-019-14082-5
Alternate JournalNat Commun
PubMed ID31949159
PubMed Central IDPMC6965647
Grant ListU54 OD020355 / OD / NIH HHS / United States
R56 AG061869 / AG / NIA NIH HHS / United States
K76 AG054772 / AG / NIA NIH HHS / United States
P01 AG014449 / AG / NIA NIH HHS / United States
U01 AG032969 / AG / NIA NIH HHS / United States
K01 AG032364 / AG / NIA NIH HHS / United States
S10 RR027990 / RR / NCRR NIH HHS / United States
R01 AG043375 / AG / NIA NIH HHS / United States
R01 MH110553 / MH / NIMH NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R21 AG028811 / AG / NIA NIH HHS / United States
P01 CA186866 / CA / NCI NIH HHS / United States
P01 AG017617 / AG / NIA NIH HHS / United States
R01 CA172546 / CA / NCI NIH HHS / United States