Redox metals and oxidative abnormalities in human prion diseases

Abstract

Prion diseases are characterized by the accumulation of diffuse and aggregated plaques of proteaseresistant prion protein (PrP) in the brains of affected individuals and animals. Whereas prion diseases in animals appear to be almost exclusively transmitted by infection, human prion diseases most often occur sporadically and, to a lesser extent, by inheritance or infection. In the sporadic cases (sporadic CreutzfeldJakob disease, sCJD), PrP-containing plaques are infrequent, whereas in transmitted (variant CJD) and inherited (Gerstmann-Straussler-Scheinker Syndrome) cases, plaques are a usual feature. In the current study, representative cases from each of the classes of human prion disease were analyzed for the presence of markers of oxidative damage that have been found in other neurodegenerative diseases. Interestingly, we found that the pattern of deposition of PrP, amyloid-b, and redox active metals was distinct for the various prion diseases. Whereas 8-hydroxyguanosine has been shown to be increased in sCJD, and inducible NOS is increased in scrapie-infected mice, well-studied markers of oxidative damage that accumulate in the lesions of other neurodegenerative diseases (such as Alzheimer's disease, progressive supranuclear palsy, and Parkinson's disease), such as heme oxygenase-1 and lipid peroxidation, were not found around PrP deposits or in vulnerable neurons. These findings suggest an important distinction in prionrelated oxidative stress, indicating that different neurodegenerative pathways are involved in different prion diseases.

Involvement of Dab1 in APP processing and β-amyloid deposition in sporadic Creutzfeldt–Jakob patients

“…We thus conclude that PrP sc may affect Dab1 phosphorylation and A production. PrP sc inoculation gives rise to a wide range of molecular responses in infected brains (Xiang et al, 2004) including in oxidative stress (Choi et al, 1998;Martin et al, 2007;Yun et al, 2006), which is also described in sCJD patients (Freixes et al, 2006;Pamplona et al, 2008;Petersen et al, 2005). Indeed, sCJD patients with PrP sc type 1 and MM polymorphism at codon 129 are characterized by faster evolution and decreased life expectancy compared with PrP sc type 2 with other polymorphisms at codon 129 (Uro-Coste et al, 2008).…”

Hemin Interactions and Alterations of the Subcellular Localization of Prion Protein

“…Notably, peroxidase activity contributes to the oxidative damage that occurs in neurodegenerative diseases (52,53). Moreover, lipid peroxidation constitutes an early pathological event of prion disease (54) and redox-active iron can be detected in PrP Sc plaques and surrounding areas (55). Hence, in pathological conditions, peroxidase activity of PrP C -hemin or PrP Sc -hemin complexes may contribute to the progression of disease.…”

Redox Control of Prion and Disease Pathogenesis

“…Markers of metal-induced oxidative stress such as products of lipid peroxidation, including free malondialdehyde (MDA) and increased levels of Fe 2þ and Fe 3þ ions, have been identified in the cerebral cortex, striatum, and brainstem of prion disease-affected human and mouse brains, supporting this assumption (5,108,109,111,171,203). The state of increased oxidative stress could result from direct toxicity by PrP-metal complexes, increased susceptibility of neuronal cells to free radicals due to the compromised function of PrP C , or a combination of both processes (22,140,141,182).…”

“…The underlying mechanism leading to the development of protein aggregates and accompanying neurotoxicity is relatively clear for some of these conditions, whereas in others, it is still debated. Recent evidence suggests the imbalance of brain metal homeostasis as a common cause of neuronal death in several of these disorders (9,45,48,60,61,70,111,148,171,203,242). It is believed that a redox-active metal interacts with a specific protein and is reduced in its presence, resulting in the generation of reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH ) that cause aggregation of the involved protein (16,206,215,224,225).…”

“…It is believed that a redox-active metal interacts with a specific protein and is reduced in its presence, resulting in the generation of reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH ) that cause aggregation of the involved protein (16,206,215,224,225). Prominent redoxactive metals that undergo this type of reaction include copper and iron, metals that are often detected in association with protein aggregates specific to AD, PD, and prion disorders (9,150,171,206,252). Whether the accumulation of these metals is a cause or consequence of the disease process is a subject of much dispute.…”