EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila

Sekiya, Michiko, Maruko-Otake, Akiko, Hearn, Stephen, Sakakibara, Yasufumi, Fujisaki, Naoki, Suzuki, Emiko, Ando, Kanae, Iijima, Koichi M. (2017) EDEM Function in ERAD Protects against Chronic ER Proteinopathy and Age-Related Physiological Decline in Drosophila. Developmental Cell, 41 (6). 652-664.e5. ISSN 1534-5807

URL: https://www.ncbi.nlm.nih.gov/pubmed/28633019
DOI: 10.1016/j.devcel.2017.05.019

Abstract

Summary The unfolded protein response (UPR), which protects cells against accumulation of misfolded proteins in the ER, is induced in several age-associated degenerative diseases. However, sustained UPR activation has negative effects on cellular functions and may worsen disease symptoms. It remains unknown whether and how UPR components can be utilized to counteract chronic ER proteinopathies. We found that promotion of ER-associated degradation (ERAD) through upregulation of ERAD-enhancing α-mannosidase-like proteins (EDEMs) protected against chronic ER proteinopathy without inducing toxicity in a Drosophila model. ERAD activity in the brain decreased with aging, and upregulation of EDEMs suppressed age-dependent behavioral decline and extended the lifespan without affecting the UPR gene expression network. Intriguingly, EDEM mannosidase activity was dispensable for these protective effects. Therefore, upregulation of EDEM function in the ERAD protects against ER proteinopathy in vivo and thus represents a potential therapeutic target for chronic diseases.

Item Type: Paper
Uncontrolled Keywords: ER stress unfolded protein response UPR ER-associated degradation ERAD ERAD-enhancing α-mannosidase-like proteins EDEMs protein misfolding neurodegeneration aging Drosophila
Subjects: organism description > animal > insect > Drosophila
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
CSHL Authors:
Communities: CSHL labs > Spector lab
Depositing User: Matt Covey
Date Deposited: 21 Jun 2017 19:46
Last Modified: 30 Jun 2017 19:57
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35011

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