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

Maria Carmen IndaSuhasini JoshiTai WangAlexander BolaenderSrinivasa GanduJohn Koren IiiAlicia Yue CheTony TaldonePengrong YanWeilin SunMohammad UddinPalak PanchalMatthew RioloSmit ShahAfsar BarlasKe XuLon Yin L ChanAlexandra GruzinovaSarah KishinevskyLorenz StuderValentina FossatiScott A NoggleJulie R WhiteElisa de StanchinaSonia SequeiraKyle H AnthoneyJohn W SteeleKatia Manova-TodorovaSujata PatilMark P S DunphyNaga Vara Kishore PillarsettyAna C PereiraHediye Erdjument-BromageThomas A NeubertAnna RodinaStephen D GinsbergNatalia De Marco GarciaWenjie LuoGabriela Chiosis
Published in: Nature communications (2020)
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.
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