<abstract xmlns="http://www.w3.org/1999/xhtml"><p>The Prion Protein (PrP) is mostly known for its role in prion diseases, where its misfolding and aggregation can cause fatal neurodegenerative conditions such as the bovine spongiform encephalopathy and human Creutzfeldt–Jakob disease. Physiologically, PrP is involved in several processes including adhesion, proliferation, differentiation and angiogenesis, but the molecular mechanisms behind its role remain unclear. PrP, due to its well-described structure, is known to be able to regulate copper homeostasis; however, copper dyshomeostasis can lead to developmental defects. We investigated PrP-dependent regulation of copper homeostasis in human endothelial cells (HUVEC) using an RNA-interference protocol. PrP knockdown did not influence cell viability in silenced HUVEC (PrPKD) compared to control cells, but significantly increased PrPKD HUVEC cells sensitivity to cytotoxic copper concentrations. A reduction of PrPKD cells reductase activity and copper ions transport capacity was observed. Furthermore, PrPKD-derived spheroids exhibited altered morphogenesis and their derived cells showed a decreased vitality 24 and 48 hours after seeding. PrPKD spheroid-derived cells also showed disrupted tubulogenesis in terms of decreased coverage area, tubule length and total nodes number on matrigel, preserving unaltered VEGF receptors expression levels. Our results highlight PrP physiological role in cellular copper homeostasis and in the angiogenesis of endothelial cells.</p></abstract>

The Prion Protein (PrP) is mostly known for its role in prion diseases, where its misfolding and aggregation can cause fatal neurodegenerative conditions such as the bovine spongiform encephalopathy and human Creutzfeldt–Jakob disease. Physiologically, PrP is involved in several processes including adhesion, proliferation, differentiation and angiogenesis, but the molecular mechanisms behind its role remain unclear. PrP, due to its well-described structure, is known to be able to regulate copper homeostasis; however, copper dyshomeostasis can lead to developmental defects. We investigated PrP-dependent regulation of copper homeostasis in human endothelial cells (HUVEC) using an RNA-interference protocol. PrP knockdown did not influence cell viability in silenced HUVEC (PrPKD) compared to control cells, but significantly increased PrPKD HUVEC cells sensitivity to cytotoxic copper concentrations. A reduction of PrPKD cells reductase activity and copper ions transport capacity was observed. Furthermore, PrPKD-derived spheroids exhibited altered morphogenesis and their derived cells showed a decreased vitality 24 and 48 hours after seeding. PrPKD spheroid-derived cells also showed disrupted tubulogenesis in terms of decreased coverage area, tubule length and total nodes number on matrigel, preserving unaltered VEGF receptors expression levels. Our results highlight PrP physiological role in cellular copper homeostasis and in the angiogenesis of endothelial cells.

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

Dept. of Biological and Environmental Science and Technology

San Raffaele -Telethon Institute for Gene Therapy

The EuroBiotech Journal

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

The Prion Protein (PrP) is mostly known for its role in prion diseases, where its misfolding and aggregation can cause fatal neurodegenerative conditions such...

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

Article Category: Research Article

Published Online: Apr 24, 2019

Page range: 57 - 70

DOI: https://doi.org/10.2478/ebtj-2019-0007

Keywords
Prion Protein, copper transport, HUVEC cells, angiogenesis, siRNA

© 2019 Lidia De Riccardis, Francesca Rizzo, Emanuela Urso, Valeria Garzarelli, Vincenza Intini, Marco Greco, Maria Chiara Maffia, Antonio Danieli, Michele Maffia, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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

Article Category: Research Article

Published Online: Apr 24, 2019

Page range: 57 - 70

DOI: https://doi.org/10.2478/ebtj-2019-0007

KeywordsPrion Protein, copper transport, HUVEC cells, angiogenesis, siRNA

© 2019 Lidia De Riccardis, Francesca Rizzo, Emanuela Urso, Valeria Garzarelli, Vincenza Intini, Marco Greco, Maria Chiara Maffia, Antonio Danieli, Michele Maffia, published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Keywords
Prion Protein, copper transport, HUVEC cells, angiogenesis, siRNA