@article{ecc37b0c727b44ee96ff384fe60dc112,
title = "Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome",
abstract = "Components of the proteostasis network malfunction in aging, and reduced protein quality control in neurons has been proposed to promote neurodegeneration. Here, we investigate the role of chaperone-mediated autophagy (CMA), a selective autophagy shown to degrade neurodegeneration-related proteins, in neuronal proteostasis. Using mouse models with systemic and neuronal-specific CMA blockage, we demonstrate that loss of neuronal CMA leads to altered neuronal function, selective changes in the neuronal metastable proteome, and proteotoxicity, all reminiscent of brain aging. Imposing CMA loss on a mouse model of Alzheimer's disease (AD) has synergistic negative effects on the proteome at risk of aggregation, thus increasing neuronal disease vulnerability and accelerating disease progression. Conversely, chemical enhancement of CMA ameliorates pathology in two different AD experimental mouse models. We conclude that functional CMA is essential for neuronal proteostasis through the maintenance of a subset of the proteome with a higher risk of misfolding than the general proteome.",
keywords = "Alzheimer's disease, aging, chaperones, chemical activators of autophagy, lysosomes, neurodegeneration, protein aggregation, proteotoxicity, supersaturated proteome, tau",
author = "Mathieu Bourdenx and Adri{\'a}n Mart{\'i}n-Segura and Aurora Scrivo and Rodriguez-Navarro, {Jose A.} and Susmita Kaushik and Inmaculada Tasset and Antonio Diaz and Storm, {Nadia J.} and Qisheng Xin and Juste, {Yves R.} and Erica Stevenson and Enrique Luengo and Clement, {Cristina C.} and Choi, {Se Joon} and Krogan, {Nevan J.} and Mosharov, {Eugene V.} and Laura Santambrogio and Fiona Grueninger and Ludovic Collin and Swaney, {Danielle L.} and David Sulzer and Evripidis Gavathiotis and Cuervo, {Ana Maria}",
note = "Funding Information: We appreciated help from Dr. Y. Cooper with the CMA activation score, Dr. P. Kirchner with dataset handling, Dr. J.J. Bravo-Cordero with actin cytoskeleton analysis, Dr. A.R. Saez with confocal microscopy, Dr. E. Bejarano with immunoblotting, and Dr. L. Ozmen with breeding design. This work was supported by the National Institutes of Health (grants AG054108 , AG021904 , AG017617 , and AG038072 to A.M.C.; grant AG031782 to A.M.C., L.S., and E.G.; grant NS100717 to A.M.C. and N.J.K.; grant NS095435 to D.S.; and grants P30 CA013330 and 1S10OD016305 [for chemical synthesis] and T32 GM007491 [for support to Y.R.J.]). This work was also supported by the JPB Foundation (to A.M.C. and D.S.), the Rainwater Charitable Foundation (to A.M.C. and E.G.), the Michael J. Fox Foundation (to A.M.C. and E.G.), the Backus Foundation (to A.M.C.), Ramon Areces (fellowship to A.M.-S.), MINECO (grant SAF78666R to J.A.R.-N. ), Charles H. Revson (fellowship CP13-00234 to J.A.R.-N.), Fulbright MINECC (fellowship to I.T.), EMBO (fellowship to N.J.S.), the Danish Council DFF (fellowship to N.J.S.), and Fundaci{\'o}n Tatiana P{\'e}rez de Guzm{\'a}n el Bueno (fellowship to E.L.). Funding Information: We appreciated help from Dr. Y. Cooper with the CMA activation score, Dr. P. Kirchner with dataset handling, Dr. J.J. Bravo-Cordero with actin cytoskeleton analysis, Dr. A.R. Saez with confocal microscopy, Dr. E. Bejarano with immunoblotting, and Dr. L. Ozmen with breeding design. This work was supported by the National Institutes of Health (grants AG054108, AG021904, AG017617, and AG038072 to A.M.C.; grant AG031782 to A.M.C. L.S. and E.G.; grant NS100717 to A.M.C. and N.J.K.; grant NS095435 to D.S.; and grants P30 CA013330 and 1S10OD016305 [for chemical synthesis] and T32 GM007491 [for support to Y.R.J.]). This work was also supported by the JPB Foundation (to A.M.C. and D.S.), the Rainwater Charitable Foundation (to A.M.C. and E.G.), the Michael J. Fox Foundation (to A.M.C. and E.G.), the Backus Foundation (to A.M.C.), Ramon Areces (fellowship to A.M.-S.), MINECO (grant SAF78666R to J.A.R.-N.), Charles H. Revson (fellowship CP13-00234 to J.A.R.-N.), Fulbright MINECC (fellowship to I.T.), EMBO (fellowship to N.J.S.), the Danish Council DFF (fellowship to N.J.S.), and Fundaci{\'o}n Tatiana P{\'e}rez de Guzm{\'a}n el Bueno (fellowship to E.L.). M.B. coordinated, designed, and performed most experiments; analyzed and interpreted data; and wrote the manuscript; A.M.-S. performed immunoblotting and immunostaining; A.S. analyzed CMA in vivo; J.A.R.-N. generated the animal colony and performed immunoblotting and immunohistochemistry; S.K. performed electron microscopy and morphometry, glycolysis analysis, and ELISA; I.T. performed immunoblot and ELISA; A.D. maintained animal colonies, performed behavior tests, and treated mice with CA; N.J.S. coordinated studies with Tg mice; Q.X. designed, synthesized, and optimized the formulation of CA; E.S. N.J.K. and D.L.S. performed and analyzed proteomics; Y.R.J. performed immunohistochemistry and qRT-PCR; E.L. performed immunohistochemistry; F.G. and L.C. contributed to planning, execution, and analysis of studies with Tg mice; C.C. and L.S. performed acetylome proteomics; S.J.C. E.M.V. and D.S. contributed to design and data interpretation; E.G. designed the CA compound and CA-related studies; and A.M.C. coordinated, designed, interpreted, and wrote the manuscript. Each corresponding author contributes unique expertise (A.M.C. on autophagy, M.B. on neuroscience, and E.G. on medicinal chemistry). A.M.C. and E.G. are cofounders and scientific advisors for Life Biosciences. A.M.C. consults for Generian Pharmaceuticals and Cognition Therapeutics. N.J.K. consults for Maze Therapeutics and Interline Therapeutics, received research support from Vir Biotechnology and F. Hoffmann-La Roche, and is a shareholder of Tenaya Therapeutics. The remaining authors declare no competing interests. CA compound is under US patent US9512092 (E.G. A.M.C. and Q.X.). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "13",
doi = "10.1016/j.cell.2021.03.048",
language = "English (US)",
volume = "184",
pages = "2696--2714.e25",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "10",
}