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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Vydáno v:	PloS one Ročník 7; číslo 2; s. e31015
Hlavní autoři:	De Franceschi, Lucia, Scardoni, Giovanni, Tomelleri, Carlo, Danek, Adrian, Walker, Ruth H., Jung, Hans H., Bader, Benedikt, Mazzucco, Sara, Dotti, Maria Teresa, Siciliano, Angela, Pantaleo, Antonella, Laudanna, Carlo
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 15.02.2012 Public Library of Science (PLoS)
Témata:	Acanthocytes - metabolism Acanthocytes - pathology Algorithms Bioinformatics Biology Blood cells Blotting, Western Chorea Chorea - metabolism Chorea - pathology Chromosomes Computational Biology Computational neuroscience Computer Science Disorders Erythrocytes Filtration Gene expression Genomes Humans Kinases Mathematical morphology McLeod syndrome Medical research Medicine Membrane proteins Morphology Movement disorders Nervous system diseases Network analysis Networks Neuroacanthocytosis - metabolism Neuroacanthocytosis - pathology Neurodegeneration Neurodegenerative diseases Neurology Ontology Patients Phenols (Class of compounds) Phosphatase Phosphorylation Phosphotransferases Protein interaction Protein Interaction Maps Protein-protein interactions Protein-Tyrosine Kinases - metabolism Proteins Proteomics Red blood cells Shortest-path problems Stability analysis Studies Syndrome Tyrosine Tyrosine - metabolism New York United States > US Italy
ISSN:	1932-6203, 1932-6203
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Performed the experiments: CT AS AP GS. Analyzed the data: CT AS AP GS LDF CL. Wrote the paper: LDF CL. Conceived and designed the study: LDF CL. Identified the patients and provided the blood samples: AD BB RHW HHJ MD SM.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0031015