Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients.

Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt-Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.

Prion diseases: what is the neurotoxic molecule?

A great deal of effort has been devoted during the past 20 years to defining the chemical nature of prions, the infectious agents responsible for transmissible spongiform encephalopathies. In contrast, much less attention has been paid to elucidating how prions actually damage the central nervous system. Although it is commonly assumed that PrP(Sc), the protein constituent of infectious prions, is the primary culprit, increasing evidence indicates that this may not be the case. Several alternative molecular forms of PrP are reasonable candidates for the neurotoxic species in prion diseases, although it is still too early to tell whether these or other ones will turn out to be the true instigating factors. The cellular pathways activated by neurotoxic forms of PrP that ultimately result in neuronal death are also being investigated, and several possible mechanisms have been uncovered, including the operation of quality control processes in the endoplasmic reticulum. Elucidating the distinction between the infectious and neurotoxic forms of PrP has important implications for designing therapy of prion diseases, as well as for understanding pathogenic mechanisms operative in other neurodegenerative disorders and the role of prion-like states in biology.

As respostas inflamatória e neuronal num modelo animal de doenças causadas por príons

O objetivo desta tese foi estudar as respostas inflamatória e neuronal em scrapie induzida experimentalmente em camundongos. Utilizando a imunocitoquimica, foram investigadas as alterações histopatológicas nos estágios iniciais da doença após a injeçäo estereotáxica de ME7 no hipocampo dorsal. As primeiras alterações histopatológicas detectadas no parênquima cerebral foram a ativaçäo de células da microglia, infiltraçäo de células T e astrocitose. Foram observadas alterações na morfologia dos neurônios nos estágios avançados da scrapie. Foi demonstrado que a expressäo da histona H1, detectada com o anticorpo ANA 108, é um indicador sensível da ativaçäo dos astrócitos e faz parte das alterações histopatológicas observadas nas doenças neurodegenerativas crônicas. Após a injeçäo intraocular de ME7, foi demonstrado que a resposta inflamatória se propaga ao longo dos axônios concomitante com a astrocitose e morte dos neurônios. As células ganglionares, as quais säo os neurônios de projeçäo da retina, degeneram nos estágios avançados da scrapie induzida pela via intraocular. As células amácrinas, as quais säo os interneurônios da retina, näo degeneram após a injeçäo intraocular de ME7. Estes resultados mostram, pela primeira vez in vivo, que duas populações de neurônios expostas ao mesmo tempo aos efeitos tóxicos da Prpsc apresentam diferente suscetibilidade a degeneraçäo. Foi demonstrado que a degeneraçäo das células ganglionares ocorre nos estágios terminais da scrapie após a injeçäo de ME7 no coliculo superior, mas näo após a injeçäo de ME7 no hipocampo dorsal. Estes resultados demonstraram que a degeneraçäo dos neurônios na scrapie depende, criticamente, da regiäo do sistema nervoso central aonde a doença inicia. Foi observada a degeneraçäo do nervo óptico na ausência de alterações na morfologia das células ganglionares indicando que a morte destes neurônios é secundária à degeneraçäo retrógada lenta dos axônios. A degeneraçäo das células ganglionares näo é devida unicamente a perda do suporte trófico causada pela morte das células alvo nas áreas de projeçäo visual. Finalmente, foi investigado o papel da degeneraçäo dos axônios na scrapie em camundongos C57BL/Wld que apresentam degeneraçäo axonal lenta. Os camundongos C57BL/Wld sobreviveram duas semanas a mais do que os camundongos C57BL/6J após a injeçäo intracerebral de ME7 (AU)