Neurometals in the Pathogenesis of Prion Diseases

Abstract

Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrP^C) into abnormal pathogenic prion protein (PrP^Sc) is critical for its infection and pathogenesis. PrP^C possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrP^C plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrP^C. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrP^C and the neurotoxicity of PrP^Sc.

Keywords: Alzheimer’s disease; amyloid; calcium homeostasis; dementia with Lewy bodies; neurotoxicity; synapse.

Figure 1

The structure and the metal-binding property of prion protein.

Figure 2

Hypothetical scheme: loss of normal functions of amyloidogenic proteins at the synapse. Normal cellular prion protein (PrP^C) is located in the postsynaptic membrane and binds to various receptors. PrP^C binds to copper (Cu), zinc (Zn), and iron (Fe) and regulates their levels at the synapse. Additionally, PrP^C acts as a ZIP Zn transporter analogue, and the ZnT-1 Zn transporter is also localized at postsynaptic membranes; both proteins control Zn levels at the synapse. PrP^C can provide Cu to amyloid precursor protein (APP) or other Cu-binding proteins at the synapse. APP is mainly localized at the presynaptic membrane, binds to Cu and/or Zn, and has the ability to convert Cu²⁺ to Cu⁺. APP also regulates Fe²⁺ efflux from cells via ferroportin. α-Synuclein is mainly localized at the presynaptic domain and binds Cu, manganese (Mn), and Fe. Both PrP^C and α-synuclein have ferrireductase activity and provide bioavailable Fe²⁺ to enzymes at the pre- and postsynaptic regions, respectively. Fe²⁺ is transported into cells by the ZIP-14 and DMT-1 complex. Other metal-binding factors such as MT-3 and carnosine (Car) are secreted into the synaptic cleft and play critical roles in the maintenance of metal homeostasis. NMDA-R; NMDA-type glutamate receptor, AMPA-R; AMPA-type glutamate receptor, FPN: ferroportin; colored circles represent glutamate, Zn, Cu, Fe, and Mn.

Figure 3

Temporal changes in intracellular calcium concentration ([Ca²⁺]_i) in GT1-7 cells after exposure to PrP peptides. Temporal changes in fluorescence intensities corresponding to changes in [Ca²⁺]_i of typical GT1-7 cells before and after exposure to each PrP peptide (20 µM). (a) PrP106–126; (b) PrP118–135; (c) scrambled PrP106–126. The arrow indicates the time of peptide addition.