Prion pathologies are a group of fatal neurodegenerative disorders that afflict mammalian species. In these diseases the cellular prion protein (PrPC) misfolds into a disease related form, known as prion (PrPSc). This misfolded protein is able to recruit and convert the physiological PrPC into pathogenic PrPSc that accumulates and leads to neuronal death. Synthetic infectious prions generated from recombinant source of PrP (recPrP) were created in the past few years with the aim of assessing if these preparations could mimic the behaviors of natural prions. Particularly, synthetic prions offer a great tool for studying both the basis of prion replication and the mechanism behind the evolution of prion strains. Indeed, recent evidence suggests that, despite the absence of nucleic acids, prions can adapt their conformation in response to changes in the context of replication. In this thesis, we have analyzed the stability of a synthetic prion isolate previously generated and named amyloid #4. In particular, amyloid #4 was either injected in wild-type mice or amplified by means of an innovative technique named Protein Misfolding Cyclic Amplfication (PMCA) which is able to mimic in vitro the process of prion conversion which occurs in vivo. Injection of raw amyloid failed to induce any disease while the injection of the PMCA amplified material induced severe prion pathology characterized by the presence of an uncommon PrPSc. When further passaged in wild-type animals such PrPSc was able to differentiate in two different isolates able to sustain different types of prion disease. These two isolates were finally assessed in PMCA and we observed the generation of an alternative conformation whose biophysical properties were different from those of both inocula, suggesting that the in vitro context of replication selectively amplified a third PrPSc isolate. Taken together these results indicate that our synthetic prion undergoes to process of evolution (selection/adaptation) dictated by the environment of its replication (bioassays VS PMCA). Synthetic prions can be used for studying prion adaptation and selection. Since all the proposed pharmacological treatments failed to cure these pathologies, understanding these behaviors of prions is of fundamental importance to design effective therapies for these devastating disorders