Chaperone-mediated autophagy: a gatekeeper of neuronal proteostasis
Autophagy. 2021-06-10; 17(8): 2040-2042
DOI: 10.1080/15548627.2021.1935007
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Bourdenx M(1)(2)(3), Gavathiotis E(2)(4)(5), Cuervo AM(1)(2)(5).
Author information:
(1)Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
(2)Institute for Aging Studies of the Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
(3)Institut des Maladies Neurodégénératives, CNRS, Université de Bordeaux, IMN, UMR 5293, F-33000 Bordeaux, France.
(4)Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY, USA.
(5)Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Different types of autophagy co-exist in all mammalian cells, however, the specific contribution of each of these autophagic pathways to the maintenance of cellular proteostasis and cellular function remains unknown. In this work, we have investigated the consequences of failure of chaperone-mediated autophagy (CMA) in neurons and compared the impact, on the neuronal proteome, of CMA loss to that of macroautophagy loss. We found that these autophagic pathways are non-redundant and that CMA is the main one responsible for maintenance of the metastable proteome (the one at risk of aggregation). We demonstrate that loss of CMA, as the one that occurs in aging, has a synergistic effect with the proteotoxicity associated with neurodegenerative conditions such as Alzheimer disease (AD) and, conversely, that, pharmacological enhancement of CMA is
effective in improving both behavior and pathology in two different AD mouse models.