Systems biology and proteomic analysis of cerebral cavernous malformation

Abstract

Cerebral cavernous malformations (CCM) are vascular anomalies caused by mutations in genes encoding KRIT1, OSM and PDCD10 proteins causing hemorrhagic stroke. We examine proteomic change of loss of CCM gene expression. Using human umbilical vein endothelial cells, label-free differential protein expression analysis with multidimensional liquid chromatography/tandem mass spectrometry was applied to three CCM protein knockdown cell lines and two control cell lines: ProteomeXchange identifier PXD000362. Principle component and cluster analyses were used to examine the differentially expressed proteins associated with CCM. The results from the five cell lines revealed 290 and 192 differentially expressed proteins (p < 0.005 and p < 0.001, respectively). Most commonly affected proteins were cytoskeleton-associated proteins, in particular myosin-9. Canonical genetic pathway analysis suggests that CCM may be a result of defective cell–cell interaction through dysregulation of cytoskeletal associated proteins. Conclusion The work explores signaling pathways that may elucidate early detection and novel therapy for CCM.

Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

“…Several omics papers, recently published, also confirmed perturbation of many genes/pathways reported here, including direct overlaps in identified genes while many other genes belonging to the same family of genes identified here. Alterations at the RNA level included the family of Integrin's (ITGB and ITGA), Moesin (MSN), protein kinase C (PRKC) and tripartite motif containing (TRIM) proteins (Edelmann et al., 2014; Koskimäki et al., 2019). TJP1 mRNAs were also shown to have direct functional relations with miRNAs isolated from CCM patients (Kar et al., 2017), validating our observation of downregulated TJP1 RNA levels in CCM1 and CCM2 KD HBMVEC.…”

“…TJP1 mRNAs were also shown to have direct functional relations with miRNAs isolated from CCM patients (Kar et al., 2017), validating our observation of downregulated TJP1 RNA levels in CCM1 and CCM2 KD HBMVEC. Proteomic confirmation included alteration of Calponin, Glyceraldehyde-3-Phosphate Dehydrogenase, Cathepsin, Glucosidase 2, Caveolin-1, Splicing Factor Proline And Glutamine Rich, Proteasome Activator Subunit 1, Trans aldolase 1, Procollagen-Lysine 2-Oxoglutarate 5-Dioxygenase 2 and Heat Shock Proteins (Edelmann et al., 2014).…”

Comparative omics of CCM signaling complex (CSC)

“…It has been demonstrated that the three CCM proteins form the CSC, which plays an essential role in the pathogenesis of CCMs when disrupted [26]. Efforts to dissect CSC signaling cascades have been made (Additional file 11) [8,10,[20][21][22][23][24][25][26], but with some contradicting outcomes. It is essential to establish comparative omics methods to assess similarities among those independent studies, which can aid in identification of potential biomarker candidates for prognostic and diagnostic applications.…”

“…A comparative database in excel (Additional files 1 and 2) was set up for the nine total available CCM cohorts that were analyzed for our comparative omics studies [8,10,[19][20][21][22][23][24][25] (Fig. 1).…”

Gene mutations in patients with hereditary cavernous malformations

“…Данные белки работают в комплексе, обеспечивая сложное взаимодействие эндотелиальных клеток с другими элементами клеточной стенки и формирование микроваскулярного русла в ткани мозга. В настоящее время ведутся исследования по расшифровке молекулярных механизмов этого взаимодействия [10][11][12].…”