RESUMO
Fatal insomnia is a rare human prion disease characterised by sleep-wake disturbances, thalamic degeneration and deposition of type 2 disease-specific prion protein (PrP(Sc)). This report details a patient with sporadic fatal insomnia who exhibited cerebral deposition of type 1 PrP(Sc) and neuropathological changes largely in the basal ganglia. Previous damage of this brain region by a surgically removed colloid cyst and the insertion of two intracerebral shunts may have influenced the distribution of PrP(Sc) through a chronic inflammatory process. These findings add to our knowledge of the phenotypic variability of human prion diseases with prominent sleep disturbances.
Assuntos
Insônia Familiar Fatal/patologia , Proteínas PrPSc/metabolismo , Western Blotting , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/patologia , Eletroencefalografia , Humanos , Imuno-Histoquímica , Insônia Familiar Fatal/genética , Insônia Familiar Fatal/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Proteínas PrPSc/genética , Tomografia Computadorizada por Raios XRESUMO
An atypical case of sporadic Creutzfeldt-Jakob disease (CJD) is described in a 78-year-old woman homozygous for methionine at codon 129 of the prion protein (PrP) gene. The neuropathological signature was the presence of PrP immunoreactive plaque-like deposits in the cerebral cortex, striatum and thalamus. Western blot analysis showed a profile of the pathological form of PrP (PrP(Sc)) previously unrecognised in sporadic CJD, marked by the absence of diglycosylated protease resistant species. These features define a novel neuropathological and molecular CJD phenotype.
Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Proteínas PrPSc/genética , Idoso , Anticorpos/imunologia , Anticorpos Monoclonais/imunologia , Antiparkinsonianos/uso terapêutico , Western Blotting , Encéfalo/imunologia , Encéfalo/patologia , Códon/genética , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/imunologia , Feminino , Humanos , Imuno-Histoquímica , Levodopa/uso terapêutico , Imageamento por Ressonância Magnética , Metionina/genética , Transtornos Parkinsonianos/tratamento farmacológico , Fenótipo , Polimorfismo Genético/genética , Proteínas PrPSc/imunologia , Valina/genéticaRESUMO
Cerebral accumulation of hyperphosphorylated tau (phospho-tau) occurs in several neurodegenerative conditions including Alzheimer disease. In prion diseases, phospho-tau deposition has been described in a rare genetic form, Gerstmann-Sträussler-Scheinker disease, but is not considered part of the neuropathological picture of Creutzfeldt-Jakob disease. Aim of this study was to investigate whether changes related to phospho-tau accumulation are present in the brain of patients with variant Creutzfeldt-Jakob disease (vCJD) that shares with Gerstmann-Sträussler-Scheinker disease abundant prion protein (PrP) deposition in amyloid form. The analysis was extended to experimental mouse models of vCJD. We detected a large number of phospho-tau-immunoreactive neuritic profiles, often clustered around PrP amyloid deposits, not only in the cerebral cortex, but also in the cerebellum of all vCJD patients examined, in the absence of Abeta. Although less constantly, phospho-tau was localized in some perikaria and dendrites. The biochemical counterpart was the presence of phospho-tau in the detergent-insoluble fraction of cerebral cortex. Phospho-tau-immunoreactive neuronal profiles were also found in association with PrP deposits in mouse models of vCJD. These findings suggest that the abnormal forms of PrP associated with vCJD trigger a tauopathy, and provide a paradigm for the early stages of tau pathology associated with cerebral amyloidoses, including Alzheimer disease.
Assuntos
Cerebelo/metabolismo , Córtex Cerebral/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Modelos Animais de Doenças , Proteínas tau/metabolismo , Adulto , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Distribuição TecidualRESUMO
The authors investigated two unrelated patients with Creutzfeldt-Jakob disease (CJD) with clinical features of sporadic CJD (sCJD) carrying one extra octapeptide repeat in the prion protein (PrP) gene (PRNP). A synaptic type PrP distribution throughout the cerebral gray matter and plaque-like PrP deposits in the subcortical gray structures were detected immunocytochemically. The different patterns of PrP deposition were associated with distinct types of protease-resistant PrP, similar to type 1 and type 2 of sCJD. The features suggest that this insertion is a pathogenic mutation.
Assuntos
Amiloide/genética , Síndrome de Creutzfeldt-Jakob/genética , Príons/genética , Precursores de Proteínas/genética , Proteínas 14-3-3 , Encéfalo/patologia , Química Encefálica , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano , Síndrome de Creutzfeldt-Jakob/diagnóstico , Eletroencefalografia , Endopeptidases/química , Heterozigoto , Homozigoto , Humanos , Immunoblotting , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Proteínas Priônicas , Príons/química , Tirosina 3-Mono-Oxigenase/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
Based on in vitro observations in scrapie-infected neuroblastoma cells, quinacrine has recently been proposed as a treatment for Creutzfeldt-Jakob disease (CJD), including a new variant CJD which is linked to contamination of food by the bovine spongiform encephalopathy (BSE) agent. The present study investigated possible mechanisms of action of quinacrine on prions. The ability of quinacrine to interact with and to reduce the protease resistance of PrP peptide aggregates and PrPres of human and animal origin were analyzed, together with its ability to inhibit the in vitro conversion of the normal prion protein (PrPc) to the abnormal form (PrPres). Furthermore, the efficiencies of quinacrine and chlorpromazine, another tricyclic compound, were examined in different in vitro models and in an experimental murine model of BSE. Quinacrine efficiently hampered de novo generation of fibrillogenic prion protein and PrPres accumulation in ScN2a cells. However, it was unable to affect the protease resistance of preexisting PrP fibrils and PrPres from brain homogenates, and a "curing" effect was obtained in ScGT1 cells only after lengthy treatment. In vivo, no detectable effect was observed in the animal model used, consistent with other recent studies and preliminary observations in humans. Despite its ability to cross the blood-brain barrier, the use of quinacrine for the treatment of CJD is questionable, at least as a monotherapy. The multistep experimental approach employed here could be used to test new therapeutic regimes before their use in human trials.