Network analysis of prion disease

Abstract

Prion diseases are transmissible neuro-degenerative diseases that arises due to conformational change of normal cellular prion protein (PrPc ) to protease-resistant isofrom (rPrPSc ). Deposition of misfolded PrPSc proteins leads to an alteration of many signaling pathways that includes immunological and apoptotic pathways and as a result, culminates in dysfunction and death of neuronal cells. Transcriptional studies have revealed some affected pathways, but it is not clear which is (are) the prime network pathway(s) that change during the disease progression and how the prime pathways are involved in cross talk with each other from the time of incubation to clinical death. To address these issues we performed network analysis on large-scale transcriptional data of differentially expressed genes obtained from whole brain in 6 different mouse prion models.We employed the notion of differential network centrality measurement to identify the potential pathways involved in disease progression. We also used cross-talk ranking method to identify core network elements involved in the cross-talk with different pathways.We identified 148 DEGs (differentially expressed genes) potentially related to the prion disease progression. Functional association of the identified genes implicated strong involvement of immunological pathways. A bow-tie structure was extracted, suggesting that the effects of prion disease on the core elements (PI3Ks and AKT) of the structure leads to potential dysfunction of the biological pathways involved. We also modeled the bow-tie network that can be used to approximate the behavior of this network during prion disease prevalence. In this study we showed using transcriptional data that neuronal dysfunction during prion disease is strongly related to immune response. We conclude that the immunological pathways occupy the network’s influential positions in the protein functional networks related to prion disease and this network-central involvement is prevalent in 5 different mouse strain-prion strain combinations.