Abstract
Accumulation of aggregates rich in an abnormally folded form of the prion protein characterize the neurodegeneration caused by transmissible spongiform encephalopathies (TSEs). The molecular triggers of plaque formation and neurodegeneration remain unknown, but analyses of TSE-infected brain homogenates and preparations enriched for abnormal prion protein suggest that reduced levels of copper and increased levels of manganese are associated with disease. The objectives of this study were to: (1) assess copper and manganese levels in healthy and TSE-infected Syrian hamster brain homogenates; (2) determine if the distribution of these metals can be mapped in TSE-infected brain tissue using X-ray photoelectron emission microscopy (X-PEEM) with synchrotron radiation; and (3) use X-PEEM to assess the relative amounts of copper and manganese in prion plaques in situ. In agreement with studies of other TSEs and species, we found reduced brain levels of copper and increased levels of manganese associated with disease in our hamster model. We also found that the in situ levels of these metals in brainstem were sufficient to image by X-PEEM. Using immunolabeled prion plaques in directly adjacent tissue sections to identify regions to image by X-PEEM, we found a statistically significant relationship of copper-manganese dysregulation in prion plaques: copper was depleted whereas manganese was enriched. These data provide evidence for prion plaques altering local transition metal distribution in the TSE-infected central nervous system.
Highlights
Transmissible spongiform encephalopathies (TSEs, prion diseases) are fatal neurodegenerative diseases that affect humans and other mammals
Changes in brain metal concentrations during the course of a transmissible spongiform encephalopathies (TSEs) infection are thought to be due to the replacement of copper for manganese in PrPSc, and metal imbalances of copper and manganese have been noted for TSEs of mice, cattle, sheep and humans [5,6,12,13,14]
Infection of hamsters with HY TSE agent changes brain copper and manganese levels to values nearly identical to those found in mice infected with the RML-strain of TSE agent [6]
Summary
Transmissible spongiform encephalopathies (TSEs, prion diseases) are fatal neurodegenerative diseases that affect humans and other mammals. The abnormally folded PrPSc molecule is derived from a normal, cellular isoform of the prion protein (PrPC). Both PrPC and PrPSc have identical amino acid sequences and covalent posttranslational modifications and differ only in secondary and higher structure. The prion protein amino acid sequence possesses an octapeptide repeat region with metal binding capacity at the N-terminus of the protein. Evidence suggests that PrPC complexes copper with a dissociation constant, Kd, in the nanomolar range and other metals, most notably manganese, may be bound [2,3]. Analysis of the metal occupancy in PrPSc in brain homogenates from TSE-infected mice indicates reduced levels of copper and increased quantities of manganese compared to PrPC from control brains, suggesting that metal binding may contribute to the mechanism of PrP C-PrPSc conversion [5,6]
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