The molecular mechanism for human metallothionein-3 to protect against the neuronal cytotoxicity of Aβ1-42 with Cu ions

Ying Luo, Yuxia Xu, Qingui Bao, Zhi-Chun Ding, Cuiqing Zhu, Zhong Xian Huang, Xiangshi Tan

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Aggregation and cytotoxicity of Aβ with redox-active metals in neuronal cells have been implicated in the progression of Alzheimer disease. Human metallothionein (MT) 3 is highly expressed in the normal human brain and is downregulated in Alzheimer disease. Zn7MT3 can protect against the neuronal toxicity of Aβ by preventing copper-mediated Aβ aggregation, abolishing the production of reactive oxygen species (ROS) and the related cellular toxicity. In this study, we intended to decipher the roles of single-domain proteins (α/β) and the α-β domain-domain interaction of Zn7MT3 to determine the molecular mechanism for protection against the neuronal cytotoxicity of Aβ1-42 with copper ions. With this in mind, the α and β single-domain proteins, heterozygous β(MT3)-α(MT1), and a linker-truncated mutant â̂†31-34 were prepared and characterized. In the presence/absence of various Zn7MT3 proteins, the Aβ 1-42-Cu2+-mediated aggregation, the production of ROS, and the cellular toxicity were investigated by transmission electron microscopy, ROS assay by means of a fluorescent probe, and SH-SY5Y cell viability, respectively. The β domain cannot abolish Aβ1-42-Cu 2+-induced aggregation, and neither the β domain nor the α domain can quench the production of ROS because of the redox cycling of Aβ-Cu2+. Similarly to wild-type Zn7MT3, the heterozygous β(MT3)-α(MT1) possesses the characteristic of alleviating Aβ1-42 aggregation and oxidative stress to neuronal cells. Therefore, the two domains through the linker Lys-Lys-Ser form a cooperative unit, and each of them is indispensable in conducting its bioactivity. The α domain plays an important role in modulating the stability of the metal-thiolate cluster, and the α-β domain-domain interaction through the linker is critical for its protective role in the brain.

Original languageEnglish (US)
Pages (from-to)39-47
Number of pages9
JournalJournal of Biological Inorganic Chemistry
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2013

Keywords

  • Alzheimer disease
  • Aβ aggregation
  • Cellular toxicity
  • ROS
  • Zinc-reconstituted human metallothionein-3

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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