NR ATPU
AU Kovacs,G.G.; Gelpi,E.; Budka,H.
TI Lysosomal alteration in neurons of human prion diseased brains
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Pathogenesis PATH-31
PT Konferenz-Poster
AB The endosomal-lysosomal system of neurons plays a role in autophagy, proteolysis, protein processing, apoptosis, antigen presentation. It might also determine specific neuronal vulnerabilites in prion disease. Here we determine the density of cathepsin D and B immunoreactive dots per unit of neuronal cytoplasmic area in cerebellar Purkinje neurons, and correlate it with subtypes of sporadic CJD according to codon 129 polymorphism and density of disease-associated prion protein, PrP[TSE]. After performing immunostaining in adjacent sections for cathepsin D, cathepsin B, and PrP[TSE], we evaluated the densities in the cytoplasm of the same 25 neurons and PrP[TSE] in the same area in each case using morphometry software. In addition, we performed double immunolabelling for PrP[TSE], cathepsin D or B. The values for cathepsin D and B immunoreactive dots was significantly (p<0.001) higher in CJD cases as in controls. For cathepsin D there was significant difference according to the codon 129 constellation, VV homozygotes harbouring the highest. For cathepsin B only the VV homozygotes showed significantly higher values. We found a positive correlation between Cathepsin D and PrP[TSE] density values. We recently expanded this investigation to frontal cortical neurons that are more vulnerable than Purkinje cells. Preliminary data suggest even more prominent alterations there. Focal colocalization of intra, peri, and extraneuronal clusters of PrP[TSE] with cathepsin D as well as co-localization within neuronal processes was also demonstrated. We conclude that (1) lysosomal activation is prominent in CJD, even in less vulnerable neuronal populations; (2) this is influenced by the morphology of PrP[TSE] deposits and codon 129 polymorphism; (3) lysosomal breakdown of PrP[TSE] is a potential route of PrP[TSE] processing and trafficking in neuronal processes, and (4) effectivity of treatment strategies aiming the lysosomal-endosomal system may differ between CJD subtypes.
AD Gabor G. Kovacs, Ellen Gelpi, Herbert Budka, Institute of Neurology, University of Vienna, Austria
SP englisch
PO Deutschland