Antioxidant and Metal Chelation-Based Therapies in the Treatment of Prion Disease

Abstract

Many neurodegenerative disorders involve the accumulation of multimeric assemblies and amyloid derived from misfolded conformers of constitutively expressed proteins. In addition, the brains of patients and experimental animals afflicted with prion disease display evidence of heightened oxidative stress and damage, as well as disturbances to transition metal homeostasis. Utilising a variety of disease model paradigms, many laboratories have demonstrated that copper can act as a cofactor in the antioxidant activity displayed by the prion protein while manganese has been implicated in the generation and stabilisation of disease-associated conformers. This and other evidence has led several groups to test dietary and chelation therapy-based regimens to manipulate brain metal concentrations in attempts to influence the progression of prion disease in experimental mice. Results have been inconsistent. This review examines published data on transition metal dyshomeostasis, free radical generation and subsequent oxidative damage in the pathogenesis of prion disease. It also comments on the efficacy of trialed therapeutics chosen to combat such deleterious changes.

Keywords: CJD; Cu; Mn; SOD2; amyloid; antioxidant; chelation; hydroxyl radical; oxidative stress; superoxide dismutase; therapy; transmissible spongiform encephalopathy.

Figure 1

Histological examination of prion infected brain tissue. The micrograph in figure A displays the extensive vacuolation commonly referred to as spongy change, here observed at the terminal stage of prion disease. This is an example of diseased hippocampal tissue obtained from a mouse model of human prion (M1000) infection [17] stained with haematoxylin and eosin. Micrograph B shows the thalamic region, adjacent to the hippocampus, of these diseased mice depicting aggregates of prion protein in the form of plaques (dark brown deposits representing immunohistochemical detection of formic acid/4 M guanidine thiocyanite-stable PrP). Original magnification 20×.

Figure 2

Schematic representation of murine prion protein (PrP^C). Wild-type PrP^C contains 4 tandem repeats approximating an octapeptide sequence, an hydrophobic core from amino acids 112 to 134 as well as 2 potential sites for glycosylation at N residues 180 and 196. Regions from 145 to 155, 175 to 193 and 200 to 219 from three alpha-helical structures, and helices II and III are disulfide bridged between C residues 178 and 213 [65]. Not to scale.

Figure 3

Model of the involvement of Mn in the generation of PrP^Sc isoforms, aggregates and plaques. PrP^Sc is able to influence the conformation of PrP^C in a template-driven manner. This altered conformation of PrP^C loses its affinity for Cu while increasing an affinity for Mn facilitating the stabilisation and accumulation of PrP^Sc and the eventual formation of PrP plaques as aggregated protein dumps. Free Cu is able to participate in deleterious redox reactions which can generate free radicals capable of damaging cellular macromolecules such as lipid membranes, proteins and DNA. PrP* represents the proposed toxic intermediate; dotted lines represent assumed associated reactions [83].