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UNIVERSITY OF MALTA
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Title: The physiological role of prion protein in neurodegenerative disease
Presenter: Dr Neville Vassallo MD MPhil
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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.