Abstract
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.
Highlights
Acanthocytes, abnormal thorny red cells in the peripheral circulation, are one of the biological hallmarks of a severe and underrecognised group of neurodegenerative group of disorders known as the neuroacanthocytosis syndromes (NA)
Sub network reconstruction and topological analysis We performed comparative proteomic analysis combined with the identification of differently tyrosine phosphorylated proteins from red cell membranes of healthy and either ChAc or McLeod syndrome (MLS) subjects (Table 1)
Since the tyrosine phosphoproteomic analysis generated a significant amount of data, whose interpretation required a network level data analysis (Supplementary Table S1, S2, S3), we carried out a topological network analysis to identify potential new signaling pathways involved in generation of acanthocytes common to MLS and ChAc
Summary
Acanthocytes, abnormal thorny red cells in the peripheral circulation, are one of the biological hallmarks of a severe and underrecognised group of neurodegenerative group of disorders known as the neuroacanthocytosis syndromes (NA). Genetic studies in the two core NA disorders, McLeod syndrome (MLS) and chorea-acanthocytosis (ChAc), have resulted in the identification of mutations on (i) the XK gene (X-chromosome) encoding for Xk protein in MLS and (ii) the VPS13A gene (chromosome 9), encoding for chorein in ChAc [1,2,3,4,5]. These two disorders share a similar Huntington disease-like phenotype including chorea, psychiatric and cognitive abnormalities and additional neuromuscular involvement. Changes in the membrane protein phosphorylation state might result in loss of red cell membrane mechanical stability and abnormal morphology [7,8,9,10,11]
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