Mutant PrPC and Prion Homologue Dpl Induced Neurodegeneration Mechanisms

Completed Research Project

Title / Titel: Mutant PrPC and Prion Homologue Dpl Induced Neurodegeneration Mechanisms

Summary / Zusammenfassung: More that fifteen years after its discovery the function of the cellular prion protein (PrPc) remains poorly understood despite intensive research. PrPc deficient mice do not show obvious abnormalities and thus fail to provide convincing information regarding the natural role of this protein. We have developed, in collaboration with the laboratory of Prof. Charles Weissmann, a neurodegeneration model induced by transgenic expression in mouse of PrP mutants lacking portions of their amino-terminus. Truncated prions induce a spontaneous and non-transmissible neurodegenerative syndrome only in animals lacking natural wt prion protein (PrPc) but not when complemented with a wt PrPc protein. It is therefore likely that neurodegeneration is triggered by interference with a cellular mechanism involving natural PrPc function. The recently discovered prion homologue Doppel (Dpl) harbours a structure strikingly similar to neurotoxic amino-truncated PrPc and also induces neurodegeneration in vivo in a PrPc dependent fashion. We are currently characterizing the neuropathological and molecular basis of truncated PrPc and Dpl using transgenic technology, biochemical tools and large scale genomic analysis.

Publications / Publikationen: Rossi, D., Cozzio, A., Flechsig, E., Klein, M. A., Aguzzi, A., and Weissmann, C. (2001). Onset of ataxia and Purkinje cell loss in PrP null mice inversely correlated with Dpl level in brain. EMBO J 20, 1-9.

Keywords / Suchbegriffe: Neurodegeneration, mutant prion protein (PrPc), Doppel (Dpl), transgenic mouse models

Project Leadership and Contacts / Projektleitung und Kontakte

Ivan Radovanovic (Project Leader)	ivan.radovanovic@pty.usz.ch
Prof. A. Aguzzi	adriano@pathol.uzh.ch

Other Links to external Webpages: http://www.uzh.ch/pathol/neuropathologie/d/index.html

In Collaboration with / In Zusammenarbeit mit

Dr. Martin Zenke, Max Delbruck Center for Molecular Medicine, Berlin

Germany