Intracellular mechanisms mediating the neuronal death and astrogliosis induced by the prion protein fragment 106-126

Prion encephalopathies include fatal diseases of the central nervous system of men and animals characterized by nerve cell loss, glial proliferation a nd deposition of amyloid fibrils into the brain. During these diseases a ce llular glycoprotein (the prion protein, PrPC) is converted, through a not y et completely clear mechanism, in an altered isoform (the prion scrapie, Pr PSc) that accumulates within the brain tissue by virtue of its resistance t o the intracellular catabolism. PrPSc is believed to be responsible for the neuronal loss that is observed in the prion disease, The PrP 106-126, a sy nthetic peptide that has been obtained from the amyloidogenic portion of th e prion protein, represents a suitable model for studying the pathogenic ro le of the PrPSc, retaining, in vitro, some characteristics of the entire pr otein, such as the capability to aggregate in fibrils, and the neurotoxicit y. In this work we present the results we have recently obtained regarding the action of the PrP 106-126 in different cellular models. We report that the PrP 106-126 induces proliferation of cortical astrocytes, as well as de generation of primary cultures of cortical neurons or of neuroectodermal st able cell lines (GH(3) cells). In particular, these two opposite effects ar e mediated by the same attitude of the peptide to interact with the L-type calcium channels: in the astrocytes, the activity of these channels seems t o be activated by PrP 106-126, while, in the cortical neurons and in the GH (3) cells, the same treatment causes a blockade of these channels causing a toxic effect. (C) 2000 ISDN. Published by Elsevier Science Ltd. All rights reserved.