Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis.
Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of...
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0031015&type=printable |
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| author | Lucia De Franceschi Giovanni Scardoni Carlo Tomelleri Adrian Danek Ruth H Walker Hans H Jung Benedikt Bader Sara Mazzucco Maria Teresa Dotti Angela Siciliano Antonella Pantaleo Carlo Laudanna |
| author_facet | Lucia De Franceschi Giovanni Scardoni Carlo Tomelleri Adrian Danek Ruth H Walker Hans H Jung Benedikt Bader Sara Mazzucco Maria Teresa Dotti Angela Siciliano Antonella Pantaleo Carlo Laudanna |
| author_sort | Lucia De Franceschi |
| collection | DOAJ |
| description | Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc. |
| format | Article |
| id | doaj-art-5d1b43fd334c44d0893cd668dec8f24f |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-5d1b43fd334c44d0893cd668dec8f24f2025-08-20T02:30:50ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0172e3101510.1371/journal.pone.0031015Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis.Lucia De FranceschiGiovanni ScardoniCarlo TomelleriAdrian DanekRuth H WalkerHans H JungBenedikt BaderSara MazzuccoMaria Teresa DottiAngela SicilianoAntonella PantaleoCarlo LaudannaAcanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0031015&type=printable |
| spellingShingle | Lucia De Franceschi Giovanni Scardoni Carlo Tomelleri Adrian Danek Ruth H Walker Hans H Jung Benedikt Bader Sara Mazzucco Maria Teresa Dotti Angela Siciliano Antonella Pantaleo Carlo Laudanna Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. PLoS ONE |
| title | Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. |
| title_full | Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. |
| title_fullStr | Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. |
| title_full_unstemmed | Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. |
| title_short | Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis. |
| title_sort | computational identification of phospho tyrosine sub networks related to acanthocyte generation in neuroacanthocytosis |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0031015&type=printable |
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