214
13.3 PrP Is Pro-survival for Cells
One of the important characteristics of cancer cell is its ability against cell death.
Many proteins against apoptosis were upregulated in cancer cells including PrP. The
first study to show that PrP is probably participating against apoptosis was shown
by Kuwahara et al. [ 48 ]. Under serum-depletion condition, hippocampal neuron
cells from PrP WT mice are more sustainable than their PrP null counterpart cells,
thus implying that PrP is a pro-survival protein under this condition. However, it
remains to be investigated why PrP null cells die faster than WT neurons, as serum-
free condition may simply imply that nutrients are important for the survival of PrP
null neuron. After that, many studies indicated that PrP protects cells against oxida-
tive stress and ischemia. The effects of PrP on oxidative stress were revealed by
showing that PrP affects Cu/Zn superoxide dismutase (SOD) activity. Increased
level of Cu/Zn SOD activity is positively correlated with augmented levels of PrP
expression, most likely due to copper incorporation into these enzymes, and were
affected by the expression levels of the PrP which binds copper with relatively high
affinity [ 49 , 50 ] showing that recombinant mouse and chicken PrP or mouse brain
tissue-purified PrP possess SOD activity. This SOD activity is acquired by PrP bind-
ing copper, and since octapeptide repeat is required to bind copper, deletion of octa-
peptide results in loss of SOD activity [ 51 ]. To further dissect which domain at the
N-terminus of PrP is important for the protective role against oxidative stress, [ 52 ]
found that the amino acids 23–50 from N2 fragment of PrP-ß cleavage are able to
initiate the protection. In addition, this protective reaction requires cell surface pro-
teins, such as glycosaminoglycans and intact lipid – raft domains – thus pointing out
a copper-independent pathway for PrP to protect against oxidative stress. In consid-
ering the low affinity between PrP and copper compared to other copper-bound
proteins, Wong et al. [ 53 ] set out to investigate if PrP in vivo can contribute to the
SOD activity. They found that the level of PrP expression is positively correlated
with the level of total SOD activity, thus supporting the idea that PrP differentially
contributes to the total SOD activity in vivo. Even if PrP does not transport copper
at physiological concentrations in the rabbit kidney epithelial cell (RK13) model
system, murine PrP expression indeed increases antioxidant enzyme activity and
glutathione levels [ 54 ]. This observation further supports a role for PrP in antioxi-
dant reaction. In addition, increased oxidative stress markers such as oxidation of
lipid and protein were detected in the brains of PrP null mice; thus, it is possible that
the antioxidant activity requires constitutive expression of PrP [ 55 , 56 ]. Protection
of neuron cells by PrP against ischemia probably is the most studied function of PrP
against oxidative stress in vivo. Maintained under normoxia condition, C57BI/6J
mice showed elevated PrP expression in cerebral microvessels and in microvessel-
depleted brain homogenate at age 6, 18, and 24 months [ 57 ], thus implicating PrP
may compensate for a loss of antioxidant activity by increasing expressing levels as
mice aging. At the same year, McLennan found that mRNA and protein of PRNP
were upregulated during hypoxia damage in neuronal processes in the penumbra
[ 58 ]. This result suggests that upregulation of PrP may be a stress response of the
X. Yang et al.