2. Academic Validation
  3. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

  • Cell. 2021 May 13;184(10):2696-2714.e25. doi: 10.1016/j.cell.2021.03.048.
Mathieu Bourdenx 1,  Adrián Martín-Segura 2,  Aurora Scrivo 2,  Jose A Rodriguez-Navarro 2,  Susmita Kaushik 2,  Inmaculada Tasset 2,  Antonio Diaz 2,  Nadia J Storm 2,  Qisheng Xin 3,  Yves R Juste 2,  Erica Stevenson 4,  Enrique Luengo 5,  Cristina C Clement 6,  Se Joon Choi 7,  Nevan J Krogan 4,  Eugene V Mosharov 7,  Laura Santambrogio 6,  Fiona Grueninger 8,  Ludovic Collin 8,  Danielle L Swaney 4,  David Sulzer 9,  Evripidis Gavathiotis 10,  Ana Maria Cuervo 11
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
PMID: 33891876 DOI: 10.1016/j.cell.2021.03.048
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.

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