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

Maria Carmen Inda, Suhasini Joshi, Tai Wang, Alexander Bolaender, Srinivasa Gandu, John Koren, Alicia Yue Che, Tony Taldone, Pengrong Yan, Weilin Sun, Mohammad Uddin, Palak Panchal, Matthew Riolo, Smit Shah, Afsar Barlas, Ke Xu, Lon Yin L. Chan, Alexandra Gruzinova, Sarah Kishinevsky, Lorenz Studer, Valentina Fossati, Scott A. Noggle, Julie R. White, Elisa Stanchina, Sonia Sequeira, Kyle H. Anthoney, John W. Steele, Katia Manova-Todorova, Sujata Patil, Mark P. Dunphy, NagaVaraKishore Pillarsetty, Ana C. Pereira, Hediye Erdjument-Bromage, Thomas A. Neubert, Anna Rodina, Stephen D. Ginsberg, Natalia Marco Garcia, Wenjie Luo () and Gabriela Chiosis ()
Additional contact information
Maria Carmen Inda: Memorial Sloan Kettering Cancer Center
Suhasini Joshi: Memorial Sloan Kettering Cancer Center
Tai Wang: Memorial Sloan Kettering Cancer Center
Alexander Bolaender: Memorial Sloan Kettering Cancer Center
Srinivasa Gandu: Memorial Sloan Kettering Cancer Center
John Koren: Memorial Sloan Kettering Cancer Center
Alicia Yue Che: Weill Cornell Medical College
Tony Taldone: Memorial Sloan Kettering Cancer Center
Pengrong Yan: Memorial Sloan Kettering Cancer Center
Weilin Sun: Memorial Sloan Kettering Cancer Center
Mohammad Uddin: Memorial Sloan Kettering Cancer Center
Palak Panchal: Memorial Sloan Kettering Cancer Center
Matthew Riolo: Memorial Sloan Kettering Cancer Center
Smit Shah: Memorial Sloan Kettering Cancer Center
Afsar Barlas: Memorial Sloan-Kettering Cancer Center
Ke Xu: Memorial Sloan-Kettering Cancer Center
Lon Yin L. Chan: Memorial Sloan Kettering Cancer Center
Alexandra Gruzinova: Memorial Sloan Kettering Cancer Center
Sarah Kishinevsky: Memorial Sloan Kettering Cancer Center
Lorenz Studer: Memorial Sloan Kettering Cancer Center
Valentina Fossati: The New York Stem Cell Foundation Research Institute
Scott A. Noggle: The New York Stem Cell Foundation Research Institute
Julie R. White: Memorial Sloan Kettering Cancer Center
Elisa Stanchina: Memorial Sloan Kettering Cancer Center
Sonia Sequeira: Memorial Sloan Kettering Cancer Center
Kyle H. Anthoney: Humboldt State University
John W. Steele: Humboldt State University
Katia Manova-Todorova: Memorial Sloan-Kettering Cancer Center
Sujata Patil: Memorial Sloan Kettering Cancer Center
Mark P. Dunphy: Memorial Sloan Kettering Cancer Center
NagaVaraKishore Pillarsetty: Memorial Sloan Kettering Cancer Center
Ana C. Pereira: Rockefeller University
Hediye Erdjument-Bromage: NYU School of Medicine
Thomas A. Neubert: NYU School of Medicine
Anna Rodina: Memorial Sloan Kettering Cancer Center
Stephen D. Ginsberg: Neuroscience & Physiology & the NYU Neuroscience Institute, NYU School of Medicine
Natalia Marco Garcia: Weill Cornell Medical College
Wenjie Luo: Weill Cornell Medical College
Gabriela Chiosis: Memorial Sloan Kettering Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14082-5

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