Identified the mechanism of action of selective chaperone-mediated autophagy activators that prevent retinal degeneration

A new work published in Nature Communications by the group of Dr. Patricia Boya at the Centro de Investigaciones Biológicas Margarita Salas (CSIC) unveils the mechanism for pharmacological targeting of chaperone-mediated autophagy activation and suggests a therapeutic strategy for retinal degeneration.

Chaperone-mediated autophagy activity is essential in the cellular defense against proteotoxicity but turns down with age. Preventing this decline in experimental genetic models has proven beneficial.

Gómez-Sintes et al. have used an experimental mouse model of retinal degeneration of clinical relevance for retinitis pigmentosa, an incurable devastating condition that results in blindness, and demonstrate that in vivo administration of the chaperone-mediated autophagy (CMA) activators, either systemically or locally through intravitreal injection, efficiently reduces retinal degeneration and preserves visual function.

Specifically, CMA activating molecules stabilize the interaction between retinoic acid receptor alpha (a known endogenous inhibitor of chaperone-mediated autophagy) and its co-repressor, nuclear receptor co-repressor 1, resulting in changes within the retinoic acid receptor alpha transcriptional program which lead to selective CMA activation. These CMA activator molecules activate this pathway in vivo and ameliorate retinal degeneration in the retinitis pigmentosa mouse model.

This work provides proof of concept for pharmacologically targeting the transcriptional mechanism of CMA regulation in a retinal degenerative setting.

The study is the result of an international collaboration with the Albert Einstein College of Medicine (NY, USA), the Universidad de Alcalá (Madrid, Spain) and the Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS, Madrid, Spain)

Reference: Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration. R. Gomez-Sintes, Q. Xin,J.I. Jiménez-Loygorri, M. McCabe, A. Diaz, T. P. Garner, X. M. Cotto-Rios, Y. Wu, S. Dong, C. A. Reynolds, B. Patel,P. de la Villa, F. Macian, P. Boya*, E. Gavathiotis*, A. M. Cuervo* (2022) Nat. Commun. 13, 4220 (2022). https://doi.org/10.1038/s41467-022-31869-1

More information:

CSIC Press Release (in Spanish): link.