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[Pharmacological studies on neurodegenerative diseases focusing on refolding and degradation of unfolded proteins in the endoplasmic reticulum].

Authors
  • Nomura, Yasuyuki
Type
Published Article
Journal
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan
Publication Date
Jan 01, 2014
Volume
134
Issue
4
Pages
537–543
Identifiers
PMID: 24694815
Source
Medline
License
Unknown

Abstract

The endoplasmic reticulum (ER) has physiological roles in the quality control of proteins. Various stresses (e.g., oxidation, aging) to the ER cause accumulation of unfolded/misfolded proteins in the ER lumen, followed by unfolded protein responses (UPR) such as refolding of unfolded protein by chaperons, ER-associated degradation (ERAD), and termination of protein synthesis. In this study, we identified protein-disulfide isomerase (PDI) upregulation by hypoxic stress in the ER of rat brains/astroglial cells. PDI overexpression attenuates hypoxia-induced neuronal apoptosis. In the brain autopsy of patients with sporadic Alzheimer's and Parkinson diseases, PDI was found to be S-nitrosylated, which reduced chaperone activity of PDI, suggesting the involvement of PDI in these diseases. In addition, we identified the novel E3 ubiquitin ligase HRD1 and observed that HRD1 activates degradation of Parkin-associated endothelin receptor-like receptor (Pael-R). HRD1 suppresses ER stress and Pael-R-induced apoptosis. Furthermore, HRD1 ubiquitinates amyloid precursor protein (APP), resulting in the decrease in amyloid β (Aβ) generation. Suppression of HRD1 expression causes APP accumulation and Aβ generation. HRD1 protein significantly decreased in the cerebral cortex of patients with Alzheimer's disease. HRD1 decrease in the brain of patients with Alzheimer's disease could be due to the insolubilization of HRD1 by oxidative stress. Subsequently, we observed that 4-phenylbutyric acid (4-PBA) possesses chaperone activity, which prevents protein aggregation and that 4-(4-methoxyphenyl)butanoic acid, a 4-PBA derivative, increases protective ability against ER stress-induced neuronal death. We believe that 4-PBA and its derivatives are potential candidates for pharmacological intervention for ER stress-induced neurodegenerative diseases.

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