NR AXRM
AU Limido,L.; Mangieri,M.; Capobianco,R.; Moda,F.; Vimercati,C.; Campagnani,I.; Catania,M.; Ghetti,B.; Giaccone,G.; Levy,E.; Tagliavini,F.
TI Role of Cystatin C in Prion Propagation and Prion Disease Pathogenesis
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.90
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Cystatin C is a cysteine protease inhibitor found in all mammalian body fluids and tissues. It is a secreted protein, but it also reaches endosomal-lysosomal compartments and inhibits cathepsin activities intracellularly. Previous studies showed that Cystatin C is overexpressed in the brain of scrapie-infected mice (Brown et al., Neuropathol Appl Neurobiol 30:555-67, 2004) and Cystatin C levels are increased in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease (Sanchez et al., Proteomics 4:2229-33, 2004). Since it is known that Cystatin C interacts with amyloid proteins such as Aß of Alzheimer's disease (Levy et al., J Neuropathol Exp Neurol 60:94-104, 2001), we have carried out an immunohistochemical study on brain tissue of patients with variant Creutzfeldt-Jakob disease (vCJD) and Gerstmann-Sträussler-
Scheinker disease (GSS) linked to different PRNP mutations (P102L, A117V, F198S). The analysis showed that Cystatin C is consistently present in PrP amyloid deposits of vCJD and GSS patients, suggesting that this protein might interact with PrPsc and play a role in disease pathogenesis. To investigate this issue, transgenic mice overexpressing human Cystatin C (Tg hu-CC) and non transgenic littermates were infected intraperitoneally with 10% vCJD brain homogenate. The incubation period and survival time were significantly shorter in Tg hu-CC mice (mean ± s.e.m.: 425 ± 11 and 453 ± 13 days) than in non transgenic littermates (516 ± 22 and 550 ±23 days). Neuropathological examination showed that the Tg hu-CC mice had larger amount of amyloid deposits than non transgenic mice; conversely, the brain regional distribution and extent of spongiform changes were similar in both groups. Immunohistochemistry revealed that Cystatin C co-localized with PrP in amyloid plaques of Tg hu-CC mice. These data indicate that high levels of Cystatin C facilitate prion disease propagation; accordingly, this protein may serve as a target for therapeutic intervention.
AD L. Limido, M. Mangieri, R. Capobianco, F. Moda, C. Vimercati, I. Campagnani, M. Catania, G. Giaccone, F. Tagliavini, National Neurological Institute, Italy; B. Ghetti, Indiana University School of Medicine, USA; E. Levy, Nathan Kline Institute, USA
SP englisch
PO Schottland