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Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):780-785. doi: 10.1073/pnas.1717877115. Epub 2018 Jan 9.

Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease.

Author information

1
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
2
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205; ssnyder@jhmi.edu bpaul8@jhmi.edu.
3
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
4
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205.

Abstract

Golgi stress response is emerging as a physiologic process of comparable importance to endoplasmic reticulum (ER) and mitochondrial stress responses. However, unlike ER stress, the identity of the signal transduction pathway involved in the Golgi stress response has been elusive. We show that the Golgi stressor monensin acts via the PKR-like ER kinase/Activating Transcription Factor 4 pathway. ATF4 is the master regulator of amino acid metabolism, which is induced during amino acid depletion and other forms of stress. One of the genes regulated by ATF4 is the biosynthetic enzyme for cysteine, cystathionine γ-lyase (CSE), which also plays central roles in maintenance of redox homeostasis. Huntington's disease (HD), a neurodegenerative disorder, is associated with disrupted cysteine metabolism caused by depletion of CSE leading to abnormal redox balance and stress response. Thus, restoring CSE function and cysteine disposition may be beneficial in HD. Accordingly, we harnessed the monensin-ATF4-signaling cascade to stimulate CSE expression by preconditioning cells with monensin, which restores cysteine metabolism and an optimal stress response in HD. These findings have implications for treatment of HD and other diseases associated with redox imbalance and dysregulated ATF4 signaling.

KEYWORDS:

ATF4; CSE; Golgi stress response; Huntington’s disease; monensin

PMID:
29317536
PMCID:
PMC5789946
DOI:
10.1073/pnas.1717877115
[Indexed for MEDLINE]
Free PMC Article

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