Cobalt induces neurodegenerative damages through Pin1 inactivation in mice and human neuroglioma cells

Fuli Zheng, Yuqing Li, Fengshun Zhang, Yi Sun, Chunyan Zheng, Zhousong Luo, Yuan Liang Wang, Michael Aschner, Hong Zheng, Liqiong Lin, Ping Cai, Wenya Shao, Zhenkun Guo, Min Zheng, Xiao Zhen Zhou, Kun Ping Lu, Siying Wu, Huangyuan Li

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cobalt is a hazardous material that has harmful effects on neurotoxicity. Excessive exposure to cobalt or inactivation of the unique proline isomerase Pin1 contributes to age-dependent neurodegeneration. However, nothing is known about the role of Pin1 in cobalt-induced neurodegeneration. Here we find that out of several hazardous materials, only cobalt dose-dependently decreased Pin1 expression and alterations in its substrates, including cis and trans phosphorylated Tau in human neuronal cells, concomitant with neurotoxicity. Cobalt-induced neurotoxicity was aggravated by Pin1 genetic or chemical inhibition, but rescued by Pin1 upregulation. Furthermore, less than 4 μg/l of blood cobalt induced dose- and age-dependent Pin1 downregulation in murine brains, ensuing neurodegenerative changes. These defects were corroborated by changes in Pin1 substrates, including cis and trans phosphorylated Tau, amyloid precursor protein, β amyloid and GSK3β. Moreover, blood Pin1 was downregulated in human hip replacement patients with median blood cobalt level of 2.514 μg/l, which is significantly less than the safety threshold of 10 μg/l, suggesting an early role Pin1 played in neurodegenerative damages. Thus, Pin1 inactivation by cobalt contributes to age-dependent neurodegeneration, revealing that cobalt is a hazardous material triggering AD-like neurodegenerative damages.

Original languageEnglish (US)
Article number126378
JournalJournal of Hazardous Materials
Volume419
DOIs
StatePublished - Oct 5 2021

Keywords

  • Cobalt
  • Neurodegeneration
  • Phosphorylated Tau (P-Tau)
  • Pin1

ASJC Scopus subject areas

  • Environmental Engineering
  • Environmental Chemistry
  • Waste Management and Disposal
  • Pollution
  • Health, Toxicology and Mutagenesis

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