Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration

Raquel Gomez-Sintes, Qisheng Xin, Juan Ignacio Jimenez-Loygorri, Mericka McCabe, Antonio Diaz, Thomas P. Garner, Xiomaris M. Cotto-Rios, Yang Wu, Shuxian Dong, Cara A. Reynolds, Bindi Patel, Pedro Villa, Fernando Macian, Patricia Boya (), Evripidis Gavathiotis () and Ana Maria Cuervo ()
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Raquel Gomez-Sintes: Albert Einstein College of Medicine
Qisheng Xin: Albert Einstein College of Medicine
Juan Ignacio Jimenez-Loygorri: Centro de Investigaciones Biológicas Margarita Salas, CSIC
Mericka McCabe: Albert Einstein College of Medicine
Antonio Diaz: Albert Einstein College of Medicine
Thomas P. Garner: Albert Einstein College of Medicine
Xiomaris M. Cotto-Rios: Albert Einstein College of Medicine
Yang Wu: Albert Einstein College of Medicine
Shuxian Dong: Albert Einstein College of Medicine
Cara A. Reynolds: Albert Einstein College of Medicine
Bindi Patel: Albert Einstein College of Medicine
Pedro Villa: Universidad de Alcalá, Madrid, Spain and Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
Fernando Macian: Institute for Aging Studies of the Department of Medicine of the Albert Einstein College of Medicine
Patricia Boya: Centro de Investigaciones Biológicas Margarita Salas, CSIC
Evripidis Gavathiotis: Institute for Aging Studies of the Department of Medicine of the Albert Einstein College of Medicine
Ana Maria Cuervo: Albert Einstein College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Chaperone-mediated autophagy activity, essential in the cellular defense against proteotoxicity, declines with age, and preventing this decline in experimental genetic models has proven beneficial. Here, we have identified the mechanism of action of selective chaperone-mediated autophagy activators previously developed by our group and have leveraged that information to generate orally bioavailable chaperone-mediated autophagy activators with favorable brain exposure. Chaperone-mediated autophagy activating molecules stabilize the interaction between retinoic acid receptor alpha - a known endogenous inhibitor of chaperone-mediated autophagy - and its co-repressor, nuclear receptor corepressor 1, resulting in changes of a discrete subset of the retinoic acid receptor alpha transcriptional program that leads to selective chaperone-mediated autophagy activation. Chaperone-mediated autophagy activators molecules activate this pathway in vivo and ameliorate retinal degeneration in a retinitis pigmentosa mouse model. Our findings reveal a mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggest a therapeutic strategy for retinal degeneration.

Date: 2022
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DOI: 10.1038/s41467-022-31869-1

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