Biological polyamines inhibit nucleic-acid-induced polymerisation of prion protein

Abstract

Nucleic-acid-induced polymerisation of prion protein, when monitored by anilino naphthalene sulfonic acid dye, shows, successively, an immediate fluorescence increase of the dye upon mixing of the reactants, followed by a lag period in which the dye fluorescence remains unchanged, and then a phase in which dye fluorescence increases with time. The biological polyamines spermine and spermidine reduce the extent of the initial fluorescence increase, increase the lag period, and reduce both the rate and the extent of increase in fluorescence intensity of the dye in the final phase of the reaction. Spermidine is less effective than spermine in all of these processes. A nearly fivefold lower concentration of spermine can inhibit polymerisation of prion protein by tRNAs compared to the same process induced by double-stranded nucleic acid. The change in the secondary structure of the globular domain of the protein induced by nucleic acid is reversed by the addition of spermine, and it prevents structural destabilization of this domain induced by nucleic acids. It is suggested that physiological event(s) that would reduce the concentrations of intracellular biological amines may make nucleic acid available to induce oligomerization and polymerisation of cellular prion protein related to prion disease.

The “Jekyll and Hyde” Actions of Nucleic Acids on the Prion-like Aggregation of Proteins

“…It was shown that PrP can bind its own mRNA, which contains G4 motifs, causing it to form a quadruplex structure under particular conditions (47). It is becoming more and more obvious that PrP binds to structured nucleic acids, and both the nucleic acid and the protein undergo structural changes when this interaction occurs (29,43,44,48,49). Indeed, different prion strains display different interactions with RNA molecules when added as conversion cofactors under cell-free conditions (50).…”

Prion Disease: Chemotherapeutic Strategies

“…[ [182][183][184][185][186][187] Stem cell therapy + Prolongs survival in mice only if given pre-clinically. [202] Tacrolimus + + Targets ER stress and calcium homeostasis.…”

“…A number of polyamines have been shown to have antiprion properties, largely through facilitation of PrP Sc clearance [182][183][184], with some effect on PrP Sc conversion as well [185,186]. Toxicity has been an issue for these compounds, but it has been reported that quaternization of the amines in polyethyleneimine and polyamidoamine dendrimers can markedly reduce the toxicity while maintaining some level of anti-prion activity in cells [187].…”

Prion Disease Therapy: Trials and Tribulations

“…Using a screening method that employs the fluorescence of anilinonaphthalene sulfonic acid (ANS), Bera and Nandi found that spermine and spermidine are able to reduce tRNA-induced polymerization of a-PrP, highlighting these compounds as possible candidates for anti-prion activities [140].…”