Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis

Episode von Medizin - Open Access LMU - Teil 20/22 von Ludwig-Maximilians-Universität München · 15. Februar 2012

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

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