title: Reductions of the components of the calreticulin/calnexin quality-control system by proteasome inhibitors and their relevance in a rodent model of Parkinson's disease.
abstract: Evidence indicates that the ubiquitin-proteasome system and the endoplasmic retculum (ER) quality-control system work in concert to ensure that proteins are correctly folded in the ER and that misfolded proteins are retrotransported to the cytosol for degradation by proteasomes. Dysfunction of either system results in developmental abnormalities and even death in animals. This study investigates whether and how proteasome inhibition impacts the components of the calreticulin (CRT)/calnexin (CNX) glycoprotein folding machinery, a typical ER protein quality-control system, in the context of early neuronal injury. Here we report that proteasome inhibitor treatments, at nonlethal levels, reduced protein levels of CRT and ERp57 but not of CNX. These treatments increased protein levels of CRT in culture media, an effect blocked by brefeldin A, an inhibitor of protein trafficking; by contrast, ERp57 was not detected in culture media. Knockdown of CRT levels alone increased the vulnerability of SH-SY5Y, a neuronal cell line, to 6-hydroxydopamine (6-OHDA) toxicity. In a rat model of Parkinson's disease, intrastriatal 6-OHDA lesions resulted in decreased levels of CRT and ERp57 in the midbrain. These findings suggest that reduction of the components of CRT/CNX glycoprotein quality-control system may play a role in neuronal injury in Parkinson's disease and other neurodegenerative disorders associated with dysfunction of the ubiquitin-proteasome system.
authors.affiliation: School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China; State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health, Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, Zhejiang, People's Republic of China.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Kuang
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Huifang
authors.initials: H
authors.lastname: Chen
authors.forename: Yiping
authors.initials: Y
authors.lastname: Li
authors.forename: Yimei
authors.initials: Y
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.forename: Ge
authors.initials: G
authors.lastname: Shan
authors.forename: Mingjie
authors.initials: M
authors.lastname: Li
authors.forename: B Joy
authors.initials: BJ
authors.lastname: Snider
authors.forename: Jia
authors.initials: J
authors.lastname: Qu
authors.forename: Steven W
authors.initials: SW
authors.lastname: Barger
authors.forename: Shengzhou
authors.initials: S
authors.lastname: Wu
mesh_terms: D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D020126:Brefeldin A / Q000494:pharmacology; D037281:Calnexin / Q000378:metabolism*; D037282:Calreticulin / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018663:Adrenergic Agents; D037282:Calreticulin; D061988:Proteasome Inhibitors; D037281:Calnexin; D020126:Brefeldin A; D016627:Oxidopamine; C513196:PDIA3 protein, rat; D019704:Protein Disulfide-Isomerases
keywords: ER quality control; Parkinson's disease; calreticulin/calnexin cycle; chaperone; endoplasmic reticulum stress; endoplasmic reticulum-associated degradation (ERAD); ubiquitin-proteasome system (UPS); unfolded protein response (UPR)