Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome

Mathieu Bourdenx, Adrián Martín-Segura, Aurora Scrivo, Jose A. Rodriguez-Navarro, Susmita Kaushik, Inmaculada Tasset, Antonio Diaz, Nadia J. Storm, Qisheng Xin, Yves R. Juste, Erica Stevenson, Enrique Luengo, Cristina C. Clement, Se Joon Choi, Nevan J. Krogan, Eugene V. Mosharov, Laura Santambrogio, Fiona Grueninger, Ludovic Collin, Danielle L. SwaneyDavid Sulzer, Evripidis Gavathiotis, Ana Maria Cuervo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2696-2714.e25
JournalCell
Volume184
Issue number10
DOIs
StatePublished - May 13 2021

Keywords

  • Alzheimer's disease
  • aging
  • chaperones
  • chemical activators of autophagy
  • lysosomes
  • neurodegeneration
  • protein aggregation
  • proteotoxicity
  • supersaturated proteome
  • tau

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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