Abstract
Prion, or PrPSc, is the pathological isoform of the cellular prion protein (PrPC) and it is the etiological agent of transmissible spongiform encephalopathies (TSE) affecting humans and animal species. The most relevant function of PrPC is its ability to bind copper ions through its flexible N-terminal moiety. This review includes an overview of the structure and function of PrPC with a focus on its ability to bind copper ions. The state-of-the-art of the role of copper in both PrPC physiology and in prion pathogenesis is also discussed. Finally, we describe the structural consequences of copper binding to the PrPC structure.
Highlights
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders that affect humans and a wide range of mammalian species
Genetic forms of prion diseases are associated with mutations in the human prion protein gene (PRNP) and comprise familial CJD, Gerstmann–Straussler–Scheinker (GSS) syndrome [4], fatal familial insomnia (FFI) [5] and prion protein cerebral amyloid angiopathy [6]
Modulation and preventing neuronal loss opening the possibility for new therapeutic approaches against prion disorders [81]. These findings underlined the role of Cu-bound to PrPC in neuroprotective mechanisms, which could be altered by the presence of ligand that interfere with copper binding, as the case of amyloid-β (Aβ) that might mediate neuronal and synaptic injury by disrupting the normal
Summary
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders that affect humans and a wide range of mammalian species. These disorders can arise sporadically, be inherited, or be acquired through infection. The neuropathological hallmarks of TSEs are spongiosis, glial proliferation, and neuronal loss They are caused by the misfolding of the physiological cellular prion protein (PrPC ) into its pathogenic scrapie isoform (PrPSc ), an insoluble and partially protease-resistant isoform that is able to propagate by interacting to and converting PrPC into nascent prion molecules [16]. The mature PrPC is found mostly in the cholesteroland sphingolipid-rich membrane domains, known as lipid rafts, which are detergent-resistant membrane domains with many important cellular receptors and other GPI-anchored proteins [24]
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