FIGURE 1: Model illustrating the cytoprotective action of spermidine in preventing spontaneous prion formation.

Spermidine inhibits the activity of histone acetyl transferases (HAT) that function to insert acetyl (Ac) groups on histone H3. This causes global gene silencing, but certain genes including autophagy-related genes (Atgs) remain acetylated thus inducing autophagic activity. Reactive oxygen species (ROS), whether endogenous or exogenous, may damage soluble proteins leading to their misfolding/aggregation. These abnormal proteins can be encapsulated by the pre-autophagosomal structure (PAS), which then fully matures into an autophagosome. The autophagosome with its cargo fuses with the vacuole where resident hydrolases can degrade the cargo and the resultant products can be channeled for biosynthesis or for energy generation. Inducing autophagy by spermidine treatment prevents prion formation by removing misfolded/oxidized proteins prior to their conversion to the prion form.