Having established that PSEN1 may be part of the mechanism linking lysosomal cholesterol dysfunction to alterations in Ca2+ homeostasis in NPC disease, we next tested the hypothesis that activation of SREBP (sterol-response element–binding protein) is responsible for the enhanced expression of key Ca2+ handling proteins, including PSEN1, in NPC1 disease (Fig. 6 A). The gene discussed is PSEN1; the disease is Niemann-Pick disease, type C1.