The data presented here are similar to that presented at recent meetings by Taylor Kimberly, Dennis Selkoe and colleagues. Collectively these studies add to the growing list of gamma-substrates. The finding that Notch ligands may be substrates for gamma-secretase is quite interesting given the essential role of PS/gamma-secretase in Notch signaling. A concern with any studies reporting novel gamma-secretase substrates that was echoed by Bart De Strooper at the Stockholm meeting this past summer is that the evidence for cleavage in many cases is only from transfected cell studies. For all candidate gamma-substrates studies, endogenous levels of substrates will be needed to confirm that these are normal events. Subsequent studies will be needed to determine whether the gamma-cleavages of novel substrates are meaningful from a physiological perspective. Preliminary reports such as this are valuable as they set the stage for follow up studies.

View all comments by Todd E. Golde