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

Cobalt is a hazardous material that has harmful effects on neurotoxicity. Excessive exposure to cobalt or inac-tivation 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 upregula-tion. Furthermore, less than 4 mu g/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 sub-strates, including cis and trans phosphorylated Tau, amyloid precursor protein, beta amyloid and GSK3 beta. Moreover, blood Pin1 was downregulated in human hip replacement patients with median blood cobalt level of 2.514 mu g/l, which is significantly less than the safety threshold of 10 mu g/l, suggesting an early role Pin1 played in neuro-degenerative damages. Thus, Pin1 inactivation by cobalt contributes to age-dependent neurodegeneration, revealing that cobalt is a hazardous material triggering AD-like neurodegenerative damages.

Automated summary

Cobalt is a hazardous material that decreases the expression of Pin1, leading to neurotoxicity and neurodegeneration. Cobalt also alters the substrates of Pin1, such as Tau, amyloid precursor protein, contributing to neurodegenerative changes.