Omi is a mammalian heat-shock protein that selectively binds and detoxifies oligomeric amyloid-β

Meng Lu Liu, Ming Jie Liu, Yan Fei Shen, Hoon Ryu, Hyeon Jin Kim, Kristina Klupsch, Julian Downward, Seong Tshool Hong

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

The cellular generation of toxic metabolites and subsequent detoxification failure can cause the uncontrolled accumulation of these metabolites in cells, leading to cellular dysfunction. Amyloid-β protein (Aβ), a normal metabolite of neurons, tends to form toxic oligomeric structures that cause neurodegeneration. It is unclear how healthy neurons control the levels of intracellular oligomeric Aβ in order to avoid neurodegeneration. Using immunochemical and biochemical studies, we show that the Aβ-binding serine protease Omi is a stress-relieving beat-shock protein that protects neurons against neurotoxic oligomeric Aβ. Through its PDZ domain, Omi binds preferentially to neurotoxic oligomeric forms of Aβ rather than non-toxic monomeric forms to detoxify oligomeric Aβ by disaggregation. This specific interaction leads not only to mutual detoxification of the pro-apoptotic activity of Omi and Aβ-induced neurotoxicity, but also to a reduction of neurotoxic-Aβ accumulation. The neuroprotective role of Omi is further supported by its upregulation during normal neurogenesis and neuronal maturation in mice, which could be in response to the increase in the generation of oligomeric Aβ during these processes. These findings provide novel and important insights into the detoxification pathway of intraneuronal oligomeric Aβ in mammals and the protective roles of Omi in neurodegeneration, suggesting a novel therapeutic target in neurodegenerative diseases.

Original languageEnglish (US)
Pages (from-to)1917-1926
Number of pages10
JournalJournal of cell science
Volume122
Issue number11
DOIs
StatePublished - Jun 1 2009

Keywords

  • Disaggregation
  • Heat-shock protein
  • HtrA2 (Omi)
  • Mutual detoxification
  • Oligomeric amyloid-β protein
  • Protein interaction

ASJC Scopus subject areas

  • Cell Biology

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    Liu, M. L., Liu, M. J., Shen, Y. F., Ryu, H., Kim, H. J., Klupsch, K., Downward, J., & Hong, S. T. (2009). Omi is a mammalian heat-shock protein that selectively binds and detoxifies oligomeric amyloid-β. Journal of cell science, 122(11), 1917-1926. https://doi.org/10.1242/jcs.042226