RÉSUMÉ

Prion diseases are fatal neurodegenerative disorders caused by altered forms of the prion protein (PrP^c). It was reported that dysregulation of cellular Ca²⁺ homeostasis is recurrent in these diseases and that scrapie-infected cells exhibit Ca²⁺ perturbation via specific impairment of N-type calcium channels. However, it is not known whether such dysfunction is secondary to the broad neuronal damage accompanying prion diseases or whether it underlies pathological interactions of prions with calcium channels. In this research, we examined this latter possibility by searching for channel binding signatures in PrP^c through structural comparison with known N-type channel blockers. To this aim, a computational method devised by us to recognize similar distributions of basic residues in protein structures enabled us to find that the bioactive groups representing the pharmacophores of ω-conotoxins GVIA and MVIIA can be overlaid onto similar residues within the PrP^c globular domain. This finding, together with the knowledge that Ca²⁺ homeostasis disruption is common to other neurodegenerative disorders, led us to search for and identify an ω-conotoxin-like pharmacophore also in the Alzheimer's Aβ(1-42) peptide. These results point to the potential ability of prions and Aβ(1-42) to bind calcium channels as the elusive neurotoxic mechanism common to seemingly unrelated fatal neuropathies.