The inferred network structure has significant predictive power for nodes which are several links away from TYROBP. We studied the enrichment of functional categories in the gene sets responding to the Tyrobp perturbation experiments, and applied Bonferroni-corrected P-values for statistical significance (Extended Experimental Procedures). Approximately 99% of the differentially expressed genes from the microglia over-expressing intact Tyrobp were down-regulated compared to the control vehicle. This set was enriched for genes involved in RNA metabolism (P=6.2e-05) and cell-cycle mitosis (P=2.7e-03). In the microglia cells over-expressing the dominant negative truncated Tyrobp, 2856 up-regulated genes were enriched for the vacuole/autophagy (P=1.7e-08) and mitochondrion (P=4.6e-04), while 559 genes involved in histone assemply (P=1.6e-31) were down-regulated. Moreover, the Tyrobp regulatory effect reflects a degree of symmetry as 658 genes, related to the vacuole/autophagy (P=5e-03), were down-regulated by active Tyrobp but up-regulated in cells expressing dominant negative truncated Tyrobp. These findings are of interest because they link the far down-stream effects of TYROPB to known molecular pathology in LOAD, such as abnormalities in the cell-cycle, mitochondrion and autophagy (Coskun et al., 2004; Webber et al., 2005). The accumulated data suggest that TYROBP may be a therapeutic target in prevention of neuronal damage in LOAD.
