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UNIVERSITY OF MALTA RESEARCH SEMINARS Abstract form Title: The physiological role of prion protein in neurodegenerative disease Presenter: Dr Neville Vassallo MD MPhil Contact address: Tel: Fax: Email: Presentation date: Abstract Department of Physiology and Biochemistry, University of Malta 21-323660 21-310577 [email protected] 21 February 2005 (approximately 200-250 words) Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of invariably fatal neurodegenerative disorders. Uniquely, they may present as sporadic, inherited, or infectious forms, all of which involve conversion of the normal cellular prion protein (PrPC) into a pathogenic likeness of itself (PrPSc). Formation of neurotoxic PrPSc and/or loss of the normal function of native PrPC result in activation of cellular pathways ultimately leading to neuronal death. Physiological PrPC is thought to be involved in protection against cell death, however the exact cellular mechanisms involved are still being explored. Using the yeast Saccharomyces cerevisiae as a cellular model, it was found that intracellular expression of the N-terminal octapeptide repeat domain of PrPC protects against copper toxicity, but does not have superoxide dismutase-like activity. In neuronal cells, a novel functional link was identified between PrPC expression and phosphatidylinositol 3kinase (PI 3-kinase) activation, a protein kinase that plays a pivotal role in cell survival. Moreover, both PI 3-kinase activation and cytoprotection by PrPC appeared to rely on copper binding to the N-terminal octapeptide of PrPC. Thus, a model is proposed in which the interaction of copper(II) with the N-terminal domain of PrPC enables transduction of a signal to PI 3-kinase; the latter, in turn, mediates downstream regulation of cell survival.