Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome.
Alzheimer’s disease
aging
chaperones
chemical activators of autophagy
lysosomes
neurodegeneration
protein aggregation
proteotoxicity
supersaturated proteome
tau
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
13 05 2021
13 05 2021
Historique:
received:
27
01
2020
revised:
03
01
2021
accepted:
23
03
2021
pubmed:
24
4
2021
medline:
22
12
2021
entrez:
23
4
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33891876
pii: S0092-8674(21)00379-2
doi: 10.1016/j.cell.2021.03.048
pmc: PMC8152331
mid: NIHMS1694173
pii:
doi:
Substances chimiques
Proteome
0
Casein Kinase I
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2696-2714.e25Subventions
Organisme : NINDS NIH HHS
ID : U54 NS100717
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG021904
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007491
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054108
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG038072
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG017617
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA013330
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG031782
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA007418
Pays : United States
Organisme : NIH HHS
ID : S10 OD016305
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG021904
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS095435
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.).
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