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

Xiu Li Kuang, Fang Liu, Huifang Chen, Yiping Li, Yimei Liu, Jian Xiao, Ge Shan, Mingjie Li, B. Joy Snider, Jia Qu, Steven W. Barger, Shengzhou Wu

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Pages (from-to)1319-1329
Number of pages11
JournalJournal of Neuroscience Research
Volume92
Issue number10
DOIs
StatePublished - Oct 2014

Keywords

  • Calreticulin/calnexin cycle
  • Chaperone
  • ER quality control
  • Endoplasmic reticulum stress
  • Endoplasmic reticulum-associated degradation (ERAD)
  • Parkinson's disease
  • Ubiquitin-proteasome system (UPS)
  • Unfolded protein response (UPR)

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