Control of Abnormal Metal-Protein Interactions in Neurodegenerative Disorders by Metallothionein-3

In the brain, zinc and copper homeostasis is regulated by a small metalloprotein, metallothionein-3 (Zn(7)MT-3), which is down-regulated in neurodegenerative diseases such as Alzheimer (AD), Creutzfeldt-Jacob and Parkinson. These disorders share common pathological hallmarks including misfolding of amyloid-beta (A beta), prion protein and alpha-synuclein, the formation of protein aggregates, abnormal metal-protein interactions and oxidative stress. In AD, Cu(II) and Zn(II) are involved in the disease progression by modulating the formation and toxicity of soluble and insoluble oligomers and aggregates of the A beta peptide. Whereas the copper-induced A beta aggregation is related to the ROS production and neurotoxicity, the zinc-induced A beta aggregation is considered neuroprotective. The protective effect of extracellular Zn(7)MT-3 from A beta toxicity in neuronal cell cultures is not understood. We show that Zn(7)MT-3 not only scavenges free Cu(II) ions, but also removes Cu(II) bound to A beta. A metal swap between Zn(7)MT-3 and soluble and aggregated A beta-Cu(II) is the underlying molecular mechanism by which the ROS production and related cellular toxicity is abolished. In this process, copper is reduced by the protein thiolates forming Cu(I)(4)Zn(4)MT-3, in which an air stable Cu(I)(4)-thiolate cluster and two disulfide bonds are present. To examine whether the discovered effect represents a general protective role of this protein in other metal-linked neurodegenerative pathologies, similar studies using prion peptides in complex with Cu(II) were conducted. Zn(7)MT-3 by a similar metal swap reaction removes abnormally bound Cu(II) from the prion protein, impeding the ROS production. This finding signifies a so far unrecognized protective role of this protein in the brain.