Prion diseases are fatal and transmissible neurodegenerative disorders linked to an aberrant conformation of the cellular prion protein (PrPc). We show that the chemical compound Suramin induced aggregation of PrP in a post‐ER/Golgi compartment and prevented further trafficking of PrPc to the outer leaflet of the plasma membrane. Instead, misfolded PrP was efficiently re‐routed to acidic compartments for intracellular degradation. In contrast to PrPSc in prion‐infected cells, PrP aggregates formed in the presence of Suramin did not accumulate, were entirely sensitive to proteolytic digestion, had distinct biophysical properties, and were not infectious. The prophylactic potential of Suramin‐induced intracellular re‐routing was tested in mice. After intraperitoneal infection with scrapie prions, peripheral application of Suramin around the time of inoculation significantly delayed onset of prion disease. Our data reveal a novel quality control mechanism for misfolded PrP isoforms and introduce a new molecular mechanism for anti‐prion compounds.

The cellular prion protein (PrP C ) is a conserved glycoprotein predominantly expressed in neuronal cells. Its purpose in living cells is still enigmatic. To elucidate on its cellular function, we performed a yeast two-hybrid screen for interactors. We used murine PrP C (amino acids 23-231) as bait to search a mouse brain cDNA expression library. Several interaction partners were identified. Three of them with a high homology to known sequences were further characterized. These candidates were the neuronal phosphoprotein synapsin Ib, the adaptor protein Grb2, and the still uncharacterized prion interactor Pint1. The in vivo interaction of the three proteins with PrP C was confirmed by co-immunoprecipitation assays with recombinant and authentic proteins in mammalian cells. The binding regions were mapped using truncated PrP constructs. As both synapsin Ib and Grb2 are implicated in neuronal signaling processes, our findings further strengthen the putative role of the prion protein in signal transduction.

The transcription factor of the cyclic AMP receptor protein/FNR family, NtcA, and the P II signaling protein play central roles in global nitrogen control in cyanobacteria. A dependence on P II for NtcA-regulated transcription, however, has not been observed. In the present investigation, we examined alterations in gene expression following nitrogen deprivation in Synechococcus elongatus strain PCC 7942 and specifically the roles of NtcA and P II . Global changes in de novo protein synthesis following combined-nitrogen deprivation were visualized by in vivo [35 S]methionine labeling and two-dimensional polyacrylamide gel electrophoresis analysis. Nearly all proteins whose synthesis responded specifically to combined-nitrogen deprivation in wild-type cells of S. elongatus failed to respond in P II -and NtcA-deficient mutants. One of the proteins whose synthesis was down-regulated in a P II -and NtcA-dependent manner was RbcS, the small subunit of RubisCO. Quantification of its mRNA revealed that the abundance of the rbcLS transcript following combined-nitrogen deprivation rapidly declined in wild-type cells but not in P II and NtcA mutant cells. To investigate further the relationship between P II and NtcA, fusions of the promotorless luxAB reporter genes to the NtcA-regulated glnB gene were constructed and these constructs were used to transform wild-type cells and P II ؊ and NtcA ؊ mutants. Determination of bioluminescence under different growth conditions showed that NtcA represses gene expression in the presence of ammonium in a P II -independent manner. By contrast, NtcA-dependent activation of glnB expression following combined-nitrogen deprivation was impaired in the absence of P II . Together, these results suggest that under conditions of combined-nitrogen deprivation, the regulation of NtcA-dependent gene expression requires the P II signal transduction protein.

We describe the shortest prion protein allele known to date. Surprisingly, it is found as a polymorphism exactly in a species (prosimian lemurs) which seems highly susceptible to oral infection with BSE-derived prions. The truncation of the prion protein we found raises several questions. First, is the truncated octarepeat structure we describe, consisting of two octarepeats, still functional in copper binding? A second question is whether this truncation is related to the remarkable oral infectibility of lemurs with BSE-derived prions. And finally, one could argue that this genotype alone might favour development of a prion disease, even in the absence of exogenous infection.