The Effect of Metal Imbalances on Scrapie Neurodegeneration

Abstract

Environmental exposure to metal appears to enhance susceptibility to Transmissible Spongiform Encephalopathies (TSEs); however, published data are not conclusive. The current study focuses on assessing the effects of copper depletion and/or manganese enhancement in the diet on susceptibility to Scrapie and this disease progression. The degree of spongiosis was the highest in the animals that received a copper- depleted diet. These observations suggest that this diet contributes to the Scrapie lesions and to the worsening of the condition in animals that have been inoculated with Scrapie. The highest intensities of GFAP immunostaining were also associated with the copper- depleted diet. Dietary supplementation with manganese had a negative effect on neuronal counts. In conclusion, this study demonstrates that certain environmental factors may aggravate neuropathological Scrapie lesions. This is consistent with reports from other neurodegenerative diseases where some metalloenzymes play a pivotal protector role against the oxidative stress associated with pathogenesis.

Copper Alters Aggregation Behavior of Prion Protein and Induces Novel Interactions between Its N- and C-terminal Regions

“…We did not observe any change in thioflavin T fluorescence with Cu 2ϩ -bound PrP(23-231) at various temperatures (16,20,25,30, and 37°C), indicating that the aggregates formed are amorphous in nature (supplemental Fig. S2B).…”

“…To whom correspondence should be addressed. reports the delay in the onset of prion disease upon removal of Cu 2ϩ by chelation (24), whereas a different study shows that Cu 2ϩ -depleted diet enhances prion disease (25). Thus, the nature and consequences of interaction of Cu 2ϩ with PrP, both in vitro and in vivo, appear to be a complex phenomenon that remains to be investigated.…”

Manganese chelation therapy extends survival in a mouse model of M1000 prion disease

“…2008). A study by Hortells et al. (2009) has demonstrated that mice fed on a copper‐depleted diet during scrapie infection displayed significantly more vacuolar lesions and activated astrocytes in selected regions of the brain.…”

“…(2009) also demonstrated that elevated dietary manganese increases PrP C expression in mice. Scrapie prion‐inoculated mice fed a manganese‐enhanced diet during the incubation period were found to have suffered more severe neuronal loss and their brains contained significantly more PrP‐containing plaques when compared with controls (Hortells et al. 2009) although this diet had no influence on the animals’ incubation periods (Mitteregger et al.…”

Low Copper and High Manganese Levels in Prion Protein Plaques

“…Dysregulation of copper-manganese homeostasis has been hypothesized to contribute to, or even cause, TSE-related pathology and death [7,8], and manipulation of metal levels has been reported to modestly prolong the incubation period in scrapie-infected mice [9,10,11]. Brains of TSE-infected humans and animals have reduced levels of copper and increased levels of manganese [5,6,12,13,14].…”