The accumulation of misfolded protein aggregates can overwhelm the ubiquitin-proteasomal system, inducing apoptosis and increasing neuronal vulnerability to subsequent insults. Most neurodegenerative diseases are associated with events of protein misfolding. ĭetailed studies of individual Hsp also suggest that they play a role in ensuring the correct protein folding of other proteins within the cells, acting as so-called "molecular chaperones". Hsp70 also antagonizes the caspase-independent mitochondrial pathway by binding directly to AIF and inhibiting its nuclear translocation. Hsp90 binds to Apaf-1 and prevents its interaction with cytochrome-c, and Hsp70 prevents cytochrome-c/Apaf-1 complex formation by interacting with caspase-9. The other two chaperones (Hsp70 and Hsp90) have also been reported to target the mitochondrial pathway at different stages. Hsp27 inhibits the activation of caspase-3, induced after cytochrome-c release from mitochondria and after the activation of death receptors such as Fas. The anti-apoptotic role of these Hsp is mediated by different mechanisms. Hsp27, Hsp70, and Hsp90 (each named according to its mass in kilodaltons) are three of the best-characterised Hsp families. For example, culture neurons derived from the central and peripheral nervous systems as well as different neuronal cell lines are protected against thermal or ischemic stress by over-expression of Hsp. It has been shown that over-expression of an individual heat shock protein (Hsp) can provide a protective effect against damaging stimuli in the same manner as can a mild Hsp-inducing stress. Nevertheless, other factors could be involved in the regulation of cell death in natural scrapie.
#ROLES OF CHAPERONE PROTEINS IN BSE PRO#
Expression profiles of other genes involved in different apoptotic pathways indicate that both pro and anti-apoptotic mechanisms are activated in prion-infected tissues. Despite the induction of Bax in scrapie brains, neurons suffering this type of Programmed Cell Death (PCD) were not observed in natural scrapie, suggesting either an extremely low number of cells undergoing apoptosis or the existence of neuroprotective mechanisms. Our group has been investigating the molecular mechanisms underlying neuronal apoptosis in ovine naturally infected with scrapie. Although various mechanisms have been proposed to explain neuronal death in prion diseases, apoptosis and autophagy are the types of cell death considered most likely to be involved. The related neurological lesions include spongiform changes in grey matter, intraneuronal vacuoles in particular nuclei of the brain stem, gliosis, and neuronal degeneration. These diseases are characterised by the accumulation in the central nervous system of an abnormally folded version (PrP Sc) of a normal cellular protein, PrP C. Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative diseases that include scrapie in sheep, bovine spongiform encephalopathy in cattle, and several human neuropathies such as Creutzfeldt-Jakob disease or fatal familial insomnia. The observed differences in gene expression and protein distribution suggest that the heat shock proteins analysed play a role in the natural form of the disease. In contrast, controls displayed little or no staining in these cells. Finally, immunohistochemistry revealed intense Hsp70 and Hsp90 immunolabelling in Purkinje cells of scrapie sheep. Changes in Hsp gene and protein expression were associated with prion protein deposition, gliosis and spongiosis rather than with apoptosis. Expression rates identified by real-time RT-PCR and western blotting were compared with the extent of classical scrapie lesions using stepwise regression. Western blotting did not reveal significant differences in Hsp90 and Hsp70 protein expression between scrapie and control animals. In contrast, HSP73 was over-expressed in diencephalons of scrapie animals. Whereas changes in transcript levels were not observed in the cerebellum or medulla oblongata, a significant decrease in HSP27 and HSP90 was detected in the prefrontal cortex. Different expression profiles were observed in the areas analysed. We analysed the gene expression and protein distribution of different members of the Hsp27, Hsp70, and Hsp90 families in the central nervous system of sheep naturally infected with scrapie. Several studies have proposed the implication of Hsp in prion diseases. These proteins can also be secreted to the extracellular medium, acting as inflammatory mediators, and their chaperone activity permits correct folding of proteins and avoids the aggregation of anomalous isoforms. Heat shock proteins (Hsp) perform cytoprotective functions such as apoptosis regulation and inflammatory response control.
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