Effects of oxidative stress on the solubility of HRD1, a ubiquitin ligase implicated in Alzheimer's disease.
The E3 ubiquitin ligase HRD1 is found in the endoplasmic reticulum membrane of brain neurons and is involved in endoplasmic reticulum-associated degradation. We previously demonstrated that suppression of HRD1 expression in neurons causes accumulation of amyloid precursor protein, resulting in amyloid β production associated with endoplasmic reticulum stress and apoptosis. Furthermore, HRD1 levels are significantly decreased in the cerebral cortex of Alzheimer's disease patients because of its insolubility. The mechanisms that affect HRD1 solubility are not well understood. We here show that HRD1 protein was insolubilized by oxidative stress but not by other Alzheimer's disease-related molecules and stressors, such as amyloid β, tau, and endoplasmic reticulum stress. Furthermore, we raise the possibility that modifications of HRD1 by 4-hydroxy-2-nonenal, an oxidative stress marker, decrease HRD1 protein solubility and the oxidative stress led to the accumulation of HRD1 into the aggresome. Thus, oxidative stress-induced HRD1 insolubilization might be involved in a vicious cycle of increased amyloid β production and amyloid β-induced oxidative stress in Alzheimer's disease pathogenesis.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Japan; Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.
Ryo
R
Saito
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Japan; Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
Masayuki
M
Kaneko
Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
Yoshihisa
Y
Kitamura
Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto, Japan.
Kazuyuki
K
Takata
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Japan.
Koichi
K
Kawada
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Japan.
Yasunobu
Y
Okuma
Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan.
Yasuyuki
Y
Nomura
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D012995:Solubility; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016875:tau Proteins; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases