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Research Paper|Volume 8, Issue 12|pp 3419—3429

Quiescin-sulfhydryl oxidase inhibits prion formation in vitro

Yi-An Zhan1,2, Romany Abskharon6,7,10,11, Yu Li1,2, Jue Yuan2, Liang Zeng1,2, Johnny Dang2, Manuel Camacho Martinez2, Zerui Wang2,12, Jacqueline Mikol8, Sylvain Lehmann9, Shizhong Bu14, Jan Steyaert6,7, Li Cui12, Robert B. Petersen2,3,4, Qingzhong Kong2,3, Gong-Xiang Wang1, Alexandre Wohlkonig6,7, Wen-Quan Zou1,2,3,5,12,13
  • 1First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi Province, The People’s Republic of China
  • 2Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
  • 3Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
  • 4Department of Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
  • 5National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
  • 6VIB Center for Structural Biology, VIB, 1050 Brussels, Belgium
  • 7Structural Biology Brussels, Vrije Universiteit Brussel (VUB), 1050 Brussels, Belgium
  • 8Hôpital Lariboisière, Service d'Anatomie et Cytologie Pathologiques, Paris, France
  • 9IRMB -Hôpital ST ELOI, CHU de Montpellier, Montpellier, France
  • 10National Institute of Oceanography and Fisheries (NIFO), 11516 Cairo, Egypt
  • 11CNS, Van Andel Research Institute, Grand Rapids, MI 49503, USA
  • 12Department of Neurology, The First Hospital of Jilin University, Changchun, Jilin Province, The People’s Republic of China
  • 13State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, The People’s Republic of China
  • 14Diabetes Research Center, Ningbo University, The People’s Republic of China

* * Equal contribution

Received: October 6, 2016Accepted: November 24, 2016Published: December 11, 2016
https://doi.org/10.18632/aging.101132

Abstract

Prions are infectious proteins that cause a group of fatal transmissible diseases in animals and humans. The scrapie isoform (PrPSc) of the cellular prion protein (PrPC) is the only known component of the prion. Several lines of evidence have suggested that the formation and molecular features of PrPSc are associated with an abnormal unfolding/refolding process. Quiescin-sulfhydryl oxidase (QSOX) plays a role in protein folding by introducing disulfides into unfolded reduced proteins. Here we report that QSOX inhibits human prion propagation in protein misfolding cyclic amplification reactions and murine prion propagation in scrapie-infected neuroblastoma cells. Moreover, QSOX preferentially binds PrPSc from prion-infected human or animal brains, but not PrPC from uninfected brains. Surface plasmon resonance of the recombinant mouse PrP (moPrP) demonstrates that the affinity of QSOX for monomer is significantly lower than that for octamer (312 nM vs 1.7 nM). QSOX exhibits much lower affinity for N-terminally truncated moPrP (PrP89-230) than for the full-length moPrP (PrP23-231) (312 nM vs 2 nM), suggesting that the N-terminal region of PrP is critical for the interaction of PrP with QSOX. Our study indicates that QSOX may play a role in prion formation, which may open new therapeutic avenues for treating prion diseases.