Identification of protein-protein interaction bridges for multiple sclerosis

Identifying and prioritizing disease-related proteins is an important scientific problem to understand disease etiology. Network science has become an important discipline to prioritize such proteins. Multiple sclerosis (MS), an autoimmune disease which still cannot be cured, is characterized by a damaging process called demyelination. Demyelination is the destruction of the crucial nerve sheath, myelin, and oligodendrocytes, the cells producing myelin, by immune cells. Identifying the proteins having special features on the network formed by the proteins of oligodendrocyte and immune cells can reveal useful information about the disease. To this end, we investigated the most significant protein pairs for the intraand intercellular protein networks that we define as bridges among the proteins providing the interaction between the two cells in demyelination. We analyzed two protein networks including the oligodendrocyte and each type of two immune cells, macrophage and T-cell. We developed a model called BriFin that prioritizes contact protein pairs using network analysis techniques and integer programming. We showed several proteins it prioritized have already been associated with MS in the relevant literature. For the oligodendrocyte-macrophage network, we showed that 77% to 100% of the proteins BriFin detected, depending on the parametrization, are MS-associated. We further experimentally investigated 4 proteins prioritized by BriFin, and observed that the mRNA expression levels of 2 out of these 4 proteins significantly decreased in a group of MS patients. We therefore here present a model, BriFin, which can be used to analyze processes where interactions of two cell types play an important role.