Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome
Cell. 2021-05-01; 184(10): 2696-2714.e25
DOI: 10.1016/j.cell.2021.03.048
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Bourdenx M(1), Martín-Segura A(2), Scrivo A(2), Rodriguez-Navarro JA(2), Kaushik S(2), Tasset I(2), Diaz A(2), Storm NJ(2), Xin Q(3), Juste YR(2), Stevenson E(4), Luengo E(5), Clement CC(6), Choi SJ(7), Krogan NJ(4), Mosharov EV(7), Santambrogio L(6), Grueninger F(8), Collin L(8), Swaney DL(4), Sulzer D(9), Gavathiotis E(10), Cuervo AM(11).
Author information:
(1)Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies of the Department of
Medicine of the Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Electronic address: .
(2)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY 10461, USA; Institute for Aging Studies of the Department of
Medicine of the Albert Einstein College of Medicine, Bronx, NY 10461, USA.
(3)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY 10461, USA; Institute for Aging Studies of the Department of
Medicine of the Albert Einstein College of Medicine, Bronx, NY 10461, USA;
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York,
NY 10461, USA.
(4)Department of Cellular Molecular Pharmacology, School of Medicine and
California Institute for Quantitative Biosciences, University of California, San
Francisco, San Francisco, CA 94158, USA; David Gladstone Institutes, San
Francisco, CA 94158, USA.
(5)Department of Pharmacology, School of Medicine, Instituto Teófilo Hernando for
Drug Discovery, Universidad Autonoma de Madrid, Madrid 28049, Spain.
(6)Department of Radiation Oncology, Englander Institute for Precision Medicine,
Weill Cornell Medicine, New York, NY 10021, USA.
(7)Department of Psychiatry, Columbia University Medical Center, New York State
Psychiatric Institute, New York, NY 10461, USA.
(8)Roche Pharma Research and Early Development (pRED), Neuro-Immunology, Roche
Innovation Center Basel, CH-4070, Switzerland.
(9)Department of Psychiatry, Columbia University Medical Center, New York State
Psychiatric Institute, New York, NY 10461, USA; Departments of Neurology and
Pharmacology, Columbia University Medical Center, New York, NY 10032, USA.
(10)Institute for Aging Studies of the Department of Medicine of the Albert
Einstein College of Medicine, Bronx, NY 10461, USA; Department of Biochemistry,
Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department
of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Electronic address: .
(11)Department of Developmental and Molecular Biology, Albert Einstein College of
Medicine, Bronx, NY 10461, USA; Institute for Aging Studies of the Department of
Medicine of the Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Electronic address: .
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.
Copyright © 2021 Elsevier Inc. All rights reserved.
Conflict of interest statement: Declaration of interests 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.).