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The Frontier Leaders seminar series is back

Jerson L. Silva on the intriguing role of prion protein

Oeiras, 01.10.10

On Friday, October 8, ITQB will host Jerson L. Silva from Universidade Federal do Rio de Janeiro for the first seminar of the second series of the ITQB PhD Program Seminars "Frontier leaders of today for the scientists of tomorrow". Jerson L. Silva, who studies the basic factors responsible for protein folding, protein-nucleic acid interactions and for the formation of biological assemblages, will talk about the intriguing interaction of prion protein with nucleic acids and glycosaminoglycans in function and disease.

Jerson da Silva is a renowned brazilian scientist awarded with a number of prizes. He is currently the Director of the Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas and coordinates the Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem (INBEB) from the Universidade Federal do Rio de Janeiro.

ITQB PhD Program Seminars: 2nd Series

ITQB auditorium

The Intriguing Interaction of Prion Protein with Nucleic Acids and Glycosaminoglycans in Function and Disease

Jerson L. Silva

Instituto de Bioquímica Médica, Centro Nacional de Ressonância Magnética Nuclear Jiri Jonas, Instituto Nacional de Ciência e Tecnologia de Biologia Estrutural e Bioimagem (INBEB), Universidade Federal do Rio de Janeiro, Brazil.



The concept that transmissible spongiform encephalopathies (TSEs) are caused only by a protein has changed the traditional paradigm that disease transmission is due solely to an agent that carries genetic information. The main hypothesis for prion diseases proposes that conversion of the cellular prion protein (PrPC) into a misfolded, b-sheet-rich isoform (PrPSc) accounts for the development of (TSE). There is substantial evidence that the infectious material consists chiefly of a protein, PrPSc, with no genomic coding material - unlike a virus particle, which has both. However, prions seem to have other accomplices that chaperone their activity in converting the PrPC into the disease-causing isoform. Among chaperone candidates, nucleic acids (NAs) and glysosaminoglycans (GAGs) are the most likely. The main hypothesis for the mechanism is that cofactor binding reduces the protein mobility and therefore makes the protein-protein interactions more likely (J Biol Chem 2001, 276: 49400-49409; Trends Biochem Sci, 2008, 33: 132-140; J Biol Chem, 2008, 283: 19616-19625). We present our recent studies that show that PrP recognizes many NAs and GAGs with high affinities, and we correlate these findings with a possible pathophysiological role for this interaction. PrP binds NAs both ex vivo and in vitro with sequence and structural selectivity, and some of the PrP:NA complexes can become proteinase K-resistant, undergoing amyloid oligomerization and conversion to a b-sheet-rich structure. These results are consistent with the hypothesis that endogenous polyanions (such as NAs and GAGs) may accelerate the rate of prion disease progression by acting as scaffolds or lattices that mediate the interaction between PrPC and PrPSc molecules. In addition to a still open possibility that NAs (especially from the host) may modulate the conversion, the recent structural characterization of a PrP:NA complex has raised the possibility of developing new diagnostic and therapeutic strategies. Recent studies showing that modified oligonucleotides, as well low-molecular-weight heparin (LMWHep), have potent anti-scrapie activities suggest their therapeutic potential and highlight the importance of obtaining structural information on PrP:NA complexes. 

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