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Cell. 2016 Jun 2;165(6):1361-1374. doi: 10.1016/j.cell.2016.05.017.

Repression of the Antioxidant NRF2 Pathway in Premature Aging.

Author information

1
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.
3
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
4
High-Throughput Imaging Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
5
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
6
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
7
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China; Beijing Institute for Brain Disorders, Beijing 100069, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: ghliu@ibp.ac.cn.
8
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal premature aging disorder. The disease is caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A, leading, through unknown mechanisms, to diverse morphological, epigenetic, and genomic damage and to mesenchymal stem cell (MSC) attrition in vivo. Using a high-throughput siRNA screen, we identify the NRF2 antioxidant pathway as a driver mechanism in HGPS. Progerin sequesters NRF2 and thereby causes its subnuclear mislocalization, resulting in impaired NRF2 transcriptional activity and consequently increased chronic oxidative stress. Suppressed NRF2 activity or increased oxidative stress is sufficient to recapitulate HGPS aging defects, whereas reactivation of NRF2 activity in HGPS patient cells reverses progerin-associated nuclear aging defects and restores in vivo viability of MSCs in an animal model. These findings identify repression of the NRF2-mediated antioxidative response as a key contributor to the premature aging phenotype.

KEYWORDS:

HGPS; NRF2; aging; oxidative stress; progerin

Comment in

PMID:
27259148
PMCID:
PMC4893198
DOI:
10.1016/j.cell.2016.05.017
[Indexed for MEDLINE]
Free PMC Article

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