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nature portfolio privacy policy advertising sigma mission library research ethics committees respective institutions imagej tools lysosomal nature chronic nature juan ignacio jimenez-loygorri author information authors targeting chaperone-mediated autophagy nature reprints boosting chaperone-mediated autophagy track chaperone-mediated autophagy deficient chaperone-mediated autophagy anti-species secondary antibody research design normal n-cor1/rarα tone anti-rabbit secondary antibody middle stabilizing n-cor1/rarα interaction open h12 conformation anti-mouse secondary antibody chaperone-mediated autophagy activation cma activation index acid-precipitable radioactivity transformed stabilize rarα/n-cor1 interaction vision research ad libitum access original author ipsc-derived retinal organoids ana maria cuervo endogenous n-cor1/rarα levels retinoic acid receptor high-content microscopy studies open conformation hispur™ ni-nta resin age-related macular degeneration mouse anti β-actin ca-treated kferq-dendra mice plasmid-based reprogramming system anykd sds-page gel nen-perkinelmer life sciences drug development program rarα-rxr hetero-dimer isopropyl-b-d-thiogalactoside retinoic acid derivatives serum free-media

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         headline:Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
         description: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. Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.
         datePublished:2022-07-21T00:00:00Z
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      headline:Targeting retinoic acid receptor alpha-corepressor interaction activates chaperone-mediated autophagy and protects against retinal degeneration
      description: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. Gomez-Sintes et al. have developed small molecules that selectively activate chaperone-mediated autophagy by stabilizing the interaction between retinoic acid receptor alpha and its co-repressor N-CoR1. They demonstrate the protective effect of boosting chaperone-mediated autophagy against retinal degeneration.
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