title: 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.
authors.affiliation: Department of Biological and Environmental Sciences and Technologies, University of Salento, SP Lecce-Monteroni, Lecce, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Urso
authors.forename: Daniela
authors.initials: D
authors.lastname: Manno
authors.forename: Antonio
authors.initials: A
authors.lastname: Serra
authors.forename: Alessandro
authors.initials: A
authors.lastname: Buccolieri
authors.forename: Antonia
authors.initials: A
authors.lastname: Rizzello
authors.forename: Antonio
authors.initials: A
authors.lastname: Danieli
authors.forename: Raffaele
authors.initials: R
authors.lastname: Acierno
authors.forename: Benedetto
authors.initials: B
authors.lastname: Salvato
authors.forename: Michele
authors.initials: M
authors.lastname: Maffia
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000172:deficiency* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D007477:Ions; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D018625:Microscopy, Atomic Force; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011328:Prions / Q000378:metabolism*; D051381:Rats; D013054:Spectrophotometry, Atomic; D013482:Superoxide Dismutase / Q000378:metabolism; D014266:Trientine / Q000494:pharmacology; D015032:Zinc / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D002614:Chelating Agents; D007477:Ions; D011328:Prions; D003300:Copper; D007501:Iron; D013482:Superoxide Dismutase; D053148:Caspase 3; D015032:Zinc; D014266:Trientine