[Pharmacological studies on neurodegenerative diseases focusing on refolding and degradation of unfolded proteins in the endoplasmic reticulum].
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.
Yokohama College of Pharmacy.
Yasuyuki
Y
Nomura
D000818:Animals; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism*; D017510:Protein Folding; D058767:Protein Unfolding; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases