RESUMEN
Animal prion diseases are a group of neurodegenerative, transmissible, and fatal disorders that affect several animal species. The causative agent, prion, is a misfolded isoform of normal cellular prion protein, which is found in cells with higher concentration in the central nervous system. This review explored the sources of infection and different natural transmission routes of animal prion diseases in susceptible populations. Chronic wasting disease in cervids and scrapie in small ruminants are prion diseases capable of maintaining themselves in susceptible populations through horizontal and vertical transmission. The other prion animal diseases can only be transmitted through food contaminated with prions. Bovine spongiform encephalopathy (BSE) is the only animal prion disease considered zoonotic. However, due to its inability to transmit within a population, it could be controlled. The emergence of atypical cases of scrapie and BSE, even the recent report of prion disease in camels, demonstrates the importance of understanding the transmission routes of prion diseases to take measures to control them and to assess the risks to human and animal health.
Asunto(s)
Enfermedades de los Bovinos , Encefalopatía Espongiforme Bovina , Enfermedades por Prión , Priones , Scrapie , Enfermedades de las Ovejas , Animales , Bovinos , Susceptibilidad a Enfermedades/veterinaria , Encefalopatía Espongiforme Bovina/metabolismo , Enfermedades por Prión/metabolismo , Enfermedades por Prión/veterinaria , Priones/metabolismo , Scrapie/metabolismo , OvinosRESUMEN
Prion-related disorders (PrDs) are fatal neurodegenerative disorders characterized by progressive neuronal impairment as well as the accumulation of an abnormally folded and protease resistant form of the cellular prion protein, termed PrP(RES). Altered endoplasmic reticulum (ER) homeostasis is associated with the occurrence of neurodegeneration in sporadic, infectious and familial forms of PrDs. The ER operates as a major intracellular calcium store, playing a crucial role in pathological events related to neuronal dysfunction and death. Here we investigated the possible impact of PrP misfolding on ER calcium homeostasis in infectious and familial models of PrDs. Neuro2A cells chronically infected with scrapie prions showed decreased ER-calcium content that correlated with a stronger upregulation of UPR-inducible chaperones, and a higher sensitivity to ER stress-induced cell death. Overexpression of the calcium pump SERCA stimulated calcium release and increased the neurotoxicity observed after exposure of cells to brain-derived infectious PrP(RES). Furthermore, expression of PrP mutants that cause hereditary Creutzfeldt-Jakob disease or fatal familial insomnia led to accumulation of PrP(RES) and their partial retention at the ER, associated with a drastic decrease of ER calcium content and higher susceptibility to ER stress. Finally, similar results were observed when a transmembrane form of PrP was expressed, which is proposed as a neurotoxic intermediate. Our results suggest that alterations in calcium homeostasis and increased susceptibility to ER stress are common pathological features of both infectious and familial PrD models.
Asunto(s)
Calcio/química , Retículo Endoplásmico/metabolismo , Priones/química , Animales , Membrana Celular/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Homeostasis , Humanos , Ratones , Chaperonas Moleculares/metabolismo , Desnaturalización Proteica , Pliegue de Proteína , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Scrapie/metabolismo , Regulación hacia ArribaRESUMEN
Prions are small proteinaceous particles that transmit scrapie and other fatal encephalopathies of humans and animals, and that appear to be devoid of nucleic acids. The only known--and perhaps the sole--component of the scrapie prion is an abnormal host-encoded protein, the scrapie prion protein PrPSc. The biosynthesis of this pathological protein in the host cell, which is thus of paramount importance to prion replication, is still poorly understood. We are studying the biosynthesis and degradation of the scrapie prion protein PrPSc and of its normal isoform PrPC in scrapie-infected rodent cells in culture. PrPC is anchored to the plasma membrane through a glycosylphosphatidylinositol (GPI) moiety. In scrapie-infected mouse neuroblastoma N2a cells, PrPSc is formed post-translationally, probably from plasma membrane PrPC, in an unknown subcellular compartment that is readily accessible from the plasma membrane. Transport along the secretory pathway is necessary for PrPSc synthesis. In contrast to PrPC, PrPSc accumulates intracellularly, primarily in secondary lysosomes. The subcellular compartment(s) in which PrPSc is formed remain to be determined.