NR AXRB
AU Legname,G.; Franciotta,D.; Barillas,S.; Sussman,J.; Furlan,R.; Pizzo,S.; Prusiner,S.B.
TI Prion Protein Paralogue Doppel Interacts with alpha2-Macroglobulin: A Plausible Mechanism for Doppel-Mediated Neurodegeneration?
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.61
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Toward understanding the functions of the cellular prion protein (PrPc) and its paralogue doppel (Dpl) in the central nervous system, we fused the Fc region of human immunoglobulin to the C-termini of these proteins. Using PrP-Fc and Dpl-Fc, we identified the restricted expression of binding partners for these molecules in the granule cell layer of the cerebellum in both wild-type and PrP-deficient mice (Legname et al., 2002). Here, we describe the identification of rat a1 inhibitor-3 (a1I-3), a plasma protease inhibitor, as an interacting partner of Dpl. Together with a1I-3, Dpl also interacts with the mouse and human homologues a2-macroglobulin (A2M) but additional studies argue that PrP does not react with A2M directly. Moreover, PrP and Dpl seem to bind strongly to each other, as demonstrated by both ELISA and Biacore studies. Based on these findings, we propose a novel paradigm in which ectopic expression of Dpl induces neurodegeneration in mice through the withdrawal of a natural inhibitor of metallo-proteases such as A2M from the extracellular matrix. While A2M has been implicated as a modifier in Alzheimer's disease (Saunders and Tanzi, 2003), it remains to be determined if it has a similar role in the prion diseases.
References
Legname G, Nelken P, Guan Z, Kanyo ZF, DeArmond SJ, Prusiner SB. 2002. Prion and doppel proteins bind to granule cells of the cerebellum. Proc. Natl. Acad. Sci. USA 99:16285-16290.
Saunders AJ, Tanzi RE. 2003. Welcome to the complex disease world Alpha2macroglobulin and Alzheimer's disease. Experimental Neurology 184:50-53.
AD G. Legname, SISSA - International School for Advanced Studies, Neurobiology Sector, Italy; D. Franciotta, University of Pavia, Neurological Institute Mondino, Italy; S. Barillas, J. Sussman, S.B. Prusiner, UCSF, IND, USA; R. Furlan, DIBIT, Neuroimmunology, Italy; S. Pizzo, Duke University Medial Center, Department of Pathology, USA
SP englisch
PO Schottland