Doppel and prion proteins : double or trouble ?

Orateur : Catherine Lemaire-Vieille (LAPM, CNRS UMR5163, UJF Grenoble )

BBIO531K : Transmissible spongiform encephalopathies are fatal neurodegeneratives disorders thought to be transmitted by self-perpetuating conformational conversion of a neuronal membrane glycoprotein (PrPc for “cellular prion protein”) into an abnormal state (PrPSc, for “scrapie prion protein”). Doppel is a protein that shares significant biochemical and structural homology with PrPc. When overexpressed, Dpl is neurotoxic and causes a neurological disease in transgenic mice models. Strikingly, Dpl neurotoxicity is counteracted and prevented by PrPc. Precisely why the overexpression of Dpl is deleterious is still unclear. Moreover, mutations within the central region of PrP have been shown to be associated with severe neurotoxic activity similar to that observed with Dpl. To further investigate this neurotoxic effect, we generated lines of transgenic mice expressing different chimeric PrP-Dpl proteins. One line of transgenic mice that express the chimeric protein at a very low level, start developing ataxia at the age of 5-7 wk. This phenotype was not counteracted by a single copy of full length-PrPc but rather by its overexpression, indicating the strong toxicity of the chimeric protein. We then identified a protein domain that plays a role in mediating Dpl-related toxicity. This could provide insights into understanding the molecular mechanisms involved in the pathogenesis of prion disease and more globally of neurodegenerative disease.

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