NR AWEY
AU Forloni,G.; Fioriti,L.; Chiesa,R.; Tagliavini,F.; Salmona,M.
TI Role of prion neurotoxicity in TSE pathogenesis
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-29
PT Konferenz-Vortrag
AB Cerebral accumulation of an altered form of the prion protein (PrPsc) is believed to cause the neuropathological changes observed in transmissible spongiform encephalopathies (TSE). The coincidence of the topological distribution of neuropathological changes and PrPsc deposits and their temporal correlation in experimental scrapie strongly suggest that PrPsc is the primary cause of neurodegeneration. However, the evidence that some prion diseases arise in the absence of detectable PrPsc has led to the hypothesis that other abnormal PrP species could be the actual proximate cause of neurodegeneration. In the past we investigated the direct neurotoxic effect of PrPsc using the synthetic peptide PrP 106-126 that induced neuronal death and glial proliferation, reproducing in vitro the main neuropathological hallmarks of prion diseases. More recently, we synthesized a peptide corresponding to the smallest amyloid subunit found in Gerstmann-Sträussler-Scheinker patient brains spanning the sequence 82-146 (PrP 82-146) that polymerizes into fibrils with the tinctorial properties of amyloid. To investigate the relationship between the structure and the biological activity of the peptide, we used non-amyloidogenic variants of PrP 82-146 with a scrambled amino acid sequence in the region 106-126 and 127-146. The results indicate that both amyloid and non-amyloid forms of PrP 82-146 are toxic to neurons, the effect being mediated by oligomeric aggregates, whereas only the amyloid was able to stimulate astroglial proliferation. Investigations also showed that the biological effects of PrP 82-146 are influenced by the expression of endogenous PrP. These results, together with recent studies using recombinant PrP and transgenic mice support a direct role of oligomeric aggregates and amyloidogenic fragments in TSE pathogenesis.
AD G. Forloni: Istituto di Ricerche Farmacologiche "Mario Negri", 20157, Milano, Italy; L. Fioriti: Istituto di Ricerche Farmacologiche "Mario Negri", 20157, Milano, Italy, and Dulbecco Telethon Institute (DTI), Italy; R. Chiesa: Dulbecco Telethon Institute (DTI), Italy; F. Tagliavini: Istituto Neurologico Nazionale "Carlo Besta", 20133, Milano, Italy
SP englisch
PO Italien