Disruption of Metal Homeostasis and the Pathogenesis of Prion Diseases

Abstract

Prion diseases are progressive neurodegenerative diseases that are associated with the conformational conversion of normal cellular prion protein (PrP C ) into abnormal pathogenic prion protein (PrP Sc ). PrP C is a metal-binding protein that is located in the synapse and possesses the ability to bind to various metals, including Cu, Zn, Mn and Fe. Moreover, increasing evidence suggests that PrP C plays essential roles in the maintenance of metal homeostasis in the synapse. Trace elements have a crucial influence on the conformational change of PrP C . Given that other disease-related proteins such as β-amyloid protein and its precursor protein (APP) in Alzheimer's disease also exist in the synapse and possess a metal-binding ability, an interaction between PrP and metals and between PrP and APP, may occur in the synapse; the resulting metal homeostasis may lead to the pathogenesis of prion diseases. Here, we review our studies and other new findings that inform the current understanding of the link between trace elements and physiological functions of PrP C and the neurotoxicity of PrP Sc .

Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions

“…Thus, it is possible that only high concentrations of metal ionsmore than a 1:1 ratiowould induce secondary structures suitable for amyloid formation. In such cases, the TSE diseases might be a result of altered Cu­(II) or Zn­(II) homeostasis. ,, On the other hand, the binding of divalent metal ions to full-length PrP C is known to induce interactions between the metal-bound OR region and the C-terminal helical domain. ,, Such interactions likely help to hold the protein structure together, and it is generally known that structured proteins must first unfold before they can misfold into β-sheet structures (or β-sheet hairpins) and begin to assemble into amyloid forms. In a PrP C variant with point mutations corresponding to genetic Creutzfeldt–Jakob disease, fatal familial insomnia, and the Gerstmann–Sträussler–Scheinker disease, the addition of Zn­(II) ions induced broadening of NMR peaks indicative of weaker interactions between the Zn­(II)-bound OR region and the C-terminal domain than in the native protein.…”

“…In such cases, the TSE diseases might be a result of altered Cu(II) or Zn(II) homeostasis. 25 , 26 , 53 On the other hand, the binding of divalent metal ions to full-length PrP C is known to induce interactions between the metal-bound OR region and the C-terminal helical domain. 28 , 95 , 102 Such interactions likely help to hold the protein structure together, and it is generally known that structured proteins must first unfold before they can misfold into β-sheet structures (or β-sheet hairpins) and begin to assemble into amyloid forms.…”

“…Among the many functions attributed to PrP C , i.e., cell signaling, antioxidation, and myelination, phylogenetic analysis indicates that PrP C is evolutionarily linked to the Zrt- and Irt-like protein (ZIP) family of divalent metal ion transporters . This suggests that one biological role for PrP C might be to regulate metal ion homeostasismetal imbalance has been suggested to be part of the pathology of prion diseases. − …”