Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

Like the examples above, 56 other transcription-related genes were found to be differentially transcribed with enhanced csecretase activity (Supplemental Material, Dataset S4). Consistent with these findings, several known substrates of the enzyme were detected on the microarray as well ( Table 2 ). This suggests a possible feedback mechanism by which the augmented processing of these substrates by c-secretase might lead to their altered transcription. The overrepresentation of genes in the clusters of enzymatic activity, such as ''kinase regulator activity'' GO0019207 and ''catalytic activity'', through four distinct GO subclusters (''isomerase activity'' GO 0016853, ''ligase activity'' GO0016874, ''hydrolase activity'' GO0016787 and ''transferase activity'' GO 00167740- Fig. 2 , red boxes), is broad in terms of the type of enzymatic activity and further shows the diversification of the downstream effects of enhanced c-secretase activity. The most complex cluster of molecular function that is overrepresented among the differentially transcribed genes identified in our microarray analysis is the GO function termed ''Binding''. This cluster is overrepresented through six subclusters and several subclusters of these ( Fig. 2 , lower part). Consistent with transcription regulation, the binding subclusters of ''nucleic acid binding'' GO0003676 and ''nucleotide binding'' GO0000166 are overrepresented. The cluster of ''ion binding'' GO0043167 is overrepresented as well as the cluster of ''protein binding'' GO0005515. A consistently overrepresented subcluster of the latter is ''cytoskeletal protein binding'' GO0008092 ( Fig. 2 ). Cytoskeletal proteins have long been known to play a role in AD and Tauopathies. They are targets of the cell polarity Wnt pathway, and their dynamics have recently been shown to be affected by AICD [26] .