Role of the Cellular Prion Protein in the Neuron Adaptation Strategy to Copper Deficiency

Abstract

Copper transporter 1 (CTR1), cellular prion protein (PrP(C)), natural resistance-associated macrophage protein 2 (NRAMP2) and ATP7A proteins control the cell absorption and efflux of copper (Cu) ions in nervous tissues upon physiological conditions. Little is known about their regulation under reduced Cu availability, a condition underlying the onset of diffused neurodegenerative disorders. In this study, rat neuron-like cells were exposed to Cu starvation for 48 h. The activation of Caspase-3 enzymes and the impairment of Cu,Zn superoxide dismutase (Cu,Zn SOD) activity depicted the initiation of a pro-apoptotic program, preliminary to the appearance of the morphological signs of apoptosis. The transcriptional response related to Cu transport proteins has been investigated. Notably, PrP(C) transcript and protein levels were consistently elevated upon Cu deficiency. The CTR1 protein amount was stable, despite a two-fold increase in the transcript amount, meaning the activation of post-translational regulatory mechanisms. NRAMP2 and ATP7A expressions were unvaried. The up-regulated PrP(C) has been demonstrated to enhance the cell Cu uptake ability by about 50% with respect to the basal transport, and so sustain the Cu delivery to the Cu,Zn SOD cuproenzymes. Conclusively, the study suggests a pivotal role for PrP(C) in the cell adaptation to Cu limitation through a direct activity of ion uptake. In this view, the PrP(C) accumulation observed in several cancer cell lines could be interpreted as a molecular marker of cell Cu deficiency and a potential target of therapeutic interventions against disorders caused by metal imbalances.

Prion protein prevents heavy metals overloading of cells and thus protects them against their toxicity

“…The upregulation of PrP expression and subsequent enhancement of Cu uptake was detected under reduced Cu availability, explained as the mechanism to sustain the copper delivery for Cu/Zn SOD (Urso et al, 2012). These results are in contrast with our data, since we have found out /1 are more sensitive to copper, manganese and nickel toxicity.…”

Physiological role of Prion Protein in Copper homeostasis and angiogenic mechanisms of endothelial cells

“…The presence of blebs at the margins of the aggregates can suggest an apoptotic induction, as confirmed by the observed reduction of the proliferation rate ( Fig. 7): this result could also be explained by the well-known protection role of PrP protein against oxidative stress (13,15). Previous studies performed in spheroids derived from prostatitis tumor cells showed that mitochondrial generated ROS induce an increase of PrP protein expression and its cellular colocalization with mitochondrial enzymes such as superoxide dismutase (SOD1) and catalase (75).…”

“…Thanks to a rapid constitutive clathrin-/cavolein-dependent process (9)(10)(11), PrP is endocyted and then recycled or degraded (12,13). The protein can also regulate intracellular copper content through its ability to bind the metal ions and promote their endocytosis (14)(15)(16)(17). In fact, the histidine residues present at the PrP N-terminal domain can bind up to 6 copper ions with low affinity (18)(19)(20) triggering their cellular internalization at the synaptic cleft (9,12,21,22).…”

Behind the Link between Copper and Angiogenesis: Established Mechanisms and an Overview on the Role of Vascular Copper Transport Systems

“…High-affinity (range: μ M- n M ) copper-binding sequences, highly conserved in mammals, are localized N-terminally [185,186] and this strongly suggests the involvement of PrP C in the homeostasis of copper [187,188,189]. In particular, several pieces of evidence support the idea of proteins as copper transporters across the plasma membrane [189,190,191,192,193,194,195]. The endothelial expression of PrP C is a controversial but intriguing research topic, since blood vessels represent an ‘obligatory gate' for prions toward the central nervous system.…”