Prion diseases are fatal
neurodegenerative disorders that affect both humans and animals. The rapid
clinical progression, change in protein conformation, cross-species transmission and massive neuronal degeneration are some key features of this devastating degenerative condition. Although the etiology is unknown, aberrant processing of cellular
prion proteins is well established in the pathogenesis of
prion diseases. Normal cellular
prion protein (PrP(c)) is highly conserved in mammals and expressed predominantly in the brain. Nevertheless, the exact function of the normal
prion protein in the CNS has not been fully elucidated.
Prion proteins may function as a
metal binding protein because
divalent cations such as
copper,
zinc and
manganese can bind to octapeptide repeat sequences in the N-terminus of PrP(c). Since the binding of these metals to the octapeptide has been proposed to influence both structural and functional properties of
prion proteins, alterations in transition
metal levels can alter the course of the disease. Furthermore, cellular
antioxidant capacity is significantly compromised due to conversion of the normal
prion protein (PrP(c)) to an abnormal
scrapie prion (PrP(sc))
protein, suggesting that oxidative stress may play a role in the neurodegenerative process of
prion diseases. The combination of imbalances in cellular transition metals and increased oxidative stress could further exacerbate the neurotoxic effect of PrP(sc). This review includes an overview of the structure and function of
prion proteins, followed by the role of metals such as
copper,
manganese and
iron in the physiological function of the PrP(c), and the possible role of transition metals in the pathogenesis of the
prion disease.