The Prion protein of scrapie origin (PrP^SC), abnormal «proteinaceous particle lacking in nucleic acids», has been proposed as the infectious agent of the Transmissible Spongiform Encephalopathies (TSE), neurodegenerative always fatal diseases of the Central Nervous System (CNS).

In spite of its acceptance, this hypothesis is weak, because it implies unorthodox properties of this protein, still lacking a demonstration. The fundamental aspects of the mechanism of inducing disease, the physiological function of the normal form of the prion protein, PrP^C, and the effectiveness of infection and of transmission processes are still controversial.

This paper proposes an alternative etiology of the TSE, as being due to impaired copper metabolism due to chronic copper deficiency. In this regard PrP^C plays a relevant specific role, but not as infectious protein.

PrP^C may function as a sensor and buffer of the neuronal copper content, both on surface and inside cells, having a role too in the trans-membrane transfer of this metalloelement. This transfer may be mediated and regulated by a copper-free /copper-loaded pool of  PrP^C itself.

The stimulation of the PrP synthesis may be due to a peptide PrP(X-231) derived from the G-terminal region of PrP, considered to be a DNA bonding protein, involved in the stimulation of PrP–gene expression. The copper loaded PrP N-terminal peptide plays a role providing this metalloelement for the activation of apo copper- dependent enzymes involved in cellular metabolism.

The pathological manifestations of TSE diseases are caused by chronic copper deficiency, resulting in a progressive loss of Cu-dependent enzymatic activities.