Transmissible spongiform encephalopathies (TSEs) are a group of fatal diseases, which affect animals and humans, caused by an abnormal isoform of the prion protein (PrP). Prions replicate in the host cell by the self-propagating refolding of the normal cell surface protein, PrP^C, into a b-sheet-rich conformer, PrP^Sc. In addition, several lines of evidence suggest that glycosaminoglycans (GAGs) and in particular heparan sulfate may play a role in the PrP^C to PrP^Sc conversion process. Endogenous GAGs are required for the binding of PrP^Sc to normal cells [1]. Though direct interaction between prion protein and heparin has been recorded, little is known about the structural features implicit in this interaction. In the present work, we developed light-scattering, fluorescence and circular dichroism (CD) measurements in order to provide information on the chemical and physical properties of the murine recombinant PrP (rPrP 23-231) interaction with low molecular weight heparin (LMWHep). We found that the Far-UV CD ellipticity values increase when rPrP 23-231:LMWHep molar ratio is below 1:0.5. Conversely a decrease in ellipticity was observed on ratios above that. This result suggests that murine prion protein loses or gains secondary structure depending on LMWHep concentration. The decrease in CD values occurs rapidly, in less than 40 seconds, and is followed by an increase in light scattering. The tryptophan fluorescence emission intensity was greatly quenched. The observed effect of LMWHep on the tryptophan fluorescence could arise from the GAG-induced conformational change in the PrP N-terminal region, affecting the environment/properties of the tryptophan groups situated in this segment. Taken together, our results indicate that the presence of LMWHep, depending on its concentration, may induce partial unfolding leading to protein oligomerization.