title: [A process of programmed cell death as a mechanisms of neuronal death in prion diseases].
abstract: Neuronal loss is a salient feature of prion diseases; however, its cause and mechanism, particularly its relationship with the accumulation of the pathogenic, protease resistant isoform PrPres of the cellular prion protein PrPc, are still unclear. A number of studies suggest that it could occur through a process of programmed cell death which is consistent with the lack of inflammation in these conditions. In this paper, we review the different techniques used to identify apoptosis of neurons, and analyse the studies demonstrating neuronal apoptosis in prion diseases, either experimentally, in animal or in human. Apoptosis of rat hippocampal neurons, in cultures exposed to a synthetic peptide homologous to the prion protein, has been identified on morphological criteria after staining by a fluorescent marker of DNA and by gel electrophoresis of neuronal DNA. Apoptosis of neurons has also been identified in vivo using in situ end labelling and electron microscopy in scrapie infected mice. In human, apoptotic neurons were identified by in situ end labelling in Creutzfeldt-Jakob Disease and in Fatal Familial Insomnia. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. Neuronal apoptosis also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II, antigens, and with axonal damage as identified by beta-amyloid protein precursor immunostaining. In contrast, there was no clear correlation between the topography and severity of neuronal apoptosis and the type, topography and abundance of prion protein deposits as demonstrated by immunohistochemistry. Similarly, within the framework of comparable phenotypes, there was no difference in the abundance and distribution of apoptotic neurons according to the aetiology whether sporadic, familial, or iatrogenic, of the disease. The pathogenetic mechanism of neuronal apoptosis remains speculative and several hypothesis have been proposed. The lack of a direct association between neuronal damage and PrPres deposition may support models of neuropathogenesis based on "loss of function" of PrPc, such as withdrawal of defined activation signals inducing programmed cell death, rather than neurotoxicity. It is also possible that PrPres is neurotoxic and the dissociation between neuronal damage and the amount of protein only reflects variations in selective neuronal vulnerability. Finally, neuronal apoptosis might be an indirect consequence of PrPres deposition. PrPres-induced dendritic or axonal damage, perhaps enhanced by consequent microglial activation, might contribute to neuronal apoptosis either due to deafferentation or to retrograde neuronal degeneration.
authors.affiliation: Hôpital Raymond Poincaré, Faculté de Médecine Paris-Ouest, Garches, France.
authors.forename: F
authors.initials: F
authors.lastname: Chrétien
authors.forename: A
authors.initials: A
authors.lastname: Dorandeu
authors.forename: H
authors.initials: H
authors.lastname: Adle-Biassette
authors.forename: T
authors.initials: T
authors.lastname: Ereau
authors.forename: L
authors.initials: L
authors.lastname: Wingertsmann
authors.forename: F
authors.initials: F
authors.lastname: Brion
authors.forename: F
authors.initials: F
authors.lastname: Gray
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000473:pathology*; D017096:Prion Diseases / Q000473:pathology*; D011328:Prions / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D051381:Rats
chemical_list: D011328:Prions; D020033:Protein Isoforms