Aggresome-Like Formation Promotes Resistance to Proteotoxicity in Cells from Long-Lived Species

© The Author(s) 2020. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..

The capacity of cells to maintain proteostasis declines with age, causing rapid accumulation of damaged proteins and protein aggregates, which plays an important role in age-related disease etiology. While our group and others have identified that proteostasis is enhanced in long-lived species, there are no data on whether this leads to better resistance to proteotoxicity. We compared the sensitivity of cells from long- (naked mole rat [NMR]) and short- (Mouse) lived species to proteotoxicity, by measuring the survival of fibroblasts under polyglutamine (polyQ) toxicity, a well-established model of protein aggregation. Additionally, to evaluate the contribution of proteostatic mechanisms to proteotoxicity resistance, we down-regulated a key protein of each mechanism (autophagy-ATG5; ubiquitin-proteasome-PSMD14; and chaperones-HSP27) in NMR fibroblasts. Furthermore, we analyzed the formation and subcellular localization of inclusions in long- and short-lived species. Here, we show that fibroblasts from long-lived species are more resistant to proteotoxicity than their short-lived counterparts. Surprisingly, this does not occur because the NMR cells have less polyQ82 protein aggregates, but rather they have an enhanced capacity to handle misfolded proteins and form protective perinuclear and aggresome-like inclusions. All three proteostatic mechanisms contribute to this resistance to polyQ toxicity but autophagy has the greatest effect. Overall, our data suggest that the resistance to proteotoxicity observed in long-lived species is not due to a lower level of protein aggregates but rather to enhanced handling of the protein aggregates through the formation of aggresome-like inclusions, a well-recognized protective mechanism against proteotoxicty.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:75

Enthalten in:

The journals of gerontology. Series A, Biological sciences and medical sciences - 75(2020), 8 vom: 13. Juli, Seite 1439-1447

Sprache:

Englisch

Beteiligte Personen:

Sunchu, Bharath [VerfasserIn]
Riordan, Ruben T [VerfasserIn]
Yu, Zhen [VerfasserIn]
Almog, Ido [VerfasserIn]
Dimas-Munoz, Jovita [VerfasserIn]
Drake, Andrew C [VerfasserIn]
Perez, Viviana I [VerfasserIn]

Links:

Volltext

Themen:

26700-71-0
Aggresomes-like inclusions
Autophagy-Related Protein 5
EC 3.4.25.1
HSP27 Heat-Shock Proteins
Journal Article
Long-lived species
Molecular Chaperones
PSMD14 protein, mouse
Peptides
Polyglutamine
Proteasome Endopeptidase Complex
Proteotoxicity
RNA, Small Interfering
Research Support, N.I.H., Extramural
Trans-Activators
Ubiquitin

Anmerkungen:

Date Completed 10.02.2021

Date Revised 10.06.2021

published: Print

Citation Status MEDLINE

doi:

10.1093/gerona/glaa069

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM310949017