NR ATPS
AU Mok,S.W.F.; Burwinkel,M.; Bamme,T.; Riemer,C.; Hsu,D.K.; Liu,F.T.; Baier,M.
TI Role of Galectin-3 in Prion Disease Development
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Pathogenesis PATH-29
PT Konferenz-Poster
AB
Galectin-3 is a multi-functional protein, which was reported to bind "advanced glycation endproducts (AGE)"-modified proteins with high affinity (1), and is highly expressed in the prion-infected central nervous system (2). Given that the disease-associated isoform of the prion-protein PrPsc was described to be AGE-modified (3), we studied the role of galectin-3 in prion infections.
Following intraperitoneal or intracerebral infections galectin-3-deficient mice survived significantly longer than similarly infected wild-type control mice.
Western-blotted semi-purified PrPsc was probed with biotinylated recombinant galectin-3 and the direct and specific interaction between these proteins was confirmed. Hence, galectin-3 is possibly a natural receptor for AGE-modified PrPsc, which potentially discriminates between AGE-modified PrPsc and other isoforms of the prion-protein. Alternatively or in addition, galectin-3 may bind to PrP via its N-terminus, which shows a weak but significant sequence homology to parts of the N-terminal domain of PrP.
Taken together, the results indicate that microglia recognize AGE-modified PrPsc via galectin-3 and suggest that the pathophysiological microglia activation during prion infections of the CNS is in part mediated by galectin-3. The data provide a link between the disease-associated chronic neuroinflammation and elements of the innate immunity, which recognize AGE-modified PrPsc and mediate subsequently cellular activation. Ongoing studies address the question whether galectin-3 expressed by monocytic cells is additionally involved in prion transport following peripheral infections.
References:
1. Vlassara H, Li YM, Imani F, Wojciechowicz D, Yang Z, Liu FT, Cerami A.
Identification of galectin-3 as a high-affinity binding protein for advanced glycation end products (AGE): a new member of the AGE-receptor complex. Mol Med. 1995, 1:634-46.
2. Riemer C, Neidhold S, Burwinkel M, Schwarz A, Schultz J, Kratzschmar J, Monning U, Baier M. Gene expression profiling of scrapie-infected brain tissue. Biochem Biophys Res Commun. 2004, 323:556-64.
3. Choi YG, Kim JI, Jeon YC, Park SJ, Choi EK, Rubenstein R, Kascsak RJ, Carp RI, Kim YS. Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies. J Biol Chem. 2004, 279:30402-9
IN Galectin-3 ist ein multifunktionelles Protein, das bei TSE-Infektionen im ZNS stark exprimiert wird und an Proteine bindet, welche an Aminogruppen bestimmter Lysine oder Arginine nichtenzymatisch über die Maillard-Reaktion zunächst reversibel und anschließend durch weitere Glykosilierung und Oxidation dauerhaft und komplex glykosiliert wurden. Interessanterweise verlängert sich die Inkubationszeit TSE-infizierter Mäuse signifikant, wenn sie kein Galectin-3 exprimieren. Also gehört auch Galectin-3 zu den Faktoren, die unabhängig vom Prionprotein bei TSE-Infektionen die Inkubationszeit beeinflussen, jedoch bei allen bisher publizierten Modellen zur Verhersage der weiteren Entwicklung der nvCJK-Fallzahlen unberücksichtigt blieben.
AD Simon Wing Fai Mok, Michael Burwinkel, Theresa Bamme (bammet@rki.de ; Phone: ++49/030/45472235), Constanze Riemer, Michael Baier, Robert Koch-Institute, Berlin, Germany; Daniel K. Hsu, Fu-Tong Liu, UC Davis, School of Medicine, Sacramento, USA
SP englisch
PO Deutschland