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Diabetes Obes Metab. 2010 Oct;12 Suppl 2:108-15. doi: 10.1111/j.1463-1326.2010.01282.x.

Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases.

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1
Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.

Abstract

The endoplasmic reticulum (ER) is a eukaryotic organelle that plays important roles in protein synthesis, folding and trafficking, calcium homoeostasis and lipid and steroid synthesis. It is the major protein synthesis compartment for secreted, plasma membrane and organelle proteins. Perturbations of ER homeostasis such as the accumulation of unfolded or misfolded proteins cause ER stress. To alleviate this stress, ER triggers an evolutionarily conserved signalling cascade called the unfolded protein response (UPR). As an initial response, the UPR aims at adapting and restoring ER function by translational attenuation, upregulation of ER chaperones and degradation of unfolded proteins. However, if the ER function is severely impaired because of excessive or prolonged exposure to stress, then the inflicted cells may undergo programmed cell death. During ER stress, unstable or partially folded mutant proteins are prevented from trafficking to their proper subcellular localizations and usually rapidly degraded. The small molecules named chemical chaperones help to stabilize these mutant proteins and facilitate their folding and proper trafficking from the ER to their final destinations. Because increasing number of studies suggest that ER stress is involved in a number of disease pathogenesis including neurodegenerative diseases, cancer, obesity, diabetes and atherosclerosis, promoting ER folding capacity through chemical chaperones emerges as a novel therapeutic approach. In this review, we provide insight into the many important functions of chemical chaperones during ER stress, their impact on the ER-stress-related pathologies and their potential as a new drug targets, especially in the context of metabolic disorders.

[Indexed for MEDLINE]

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