Lysosomal Ca2+ homeostasis: Role in pathogenesis of lysosomal storage diseases

Disrupted cellular Ca2+ signaling is believed to play a role in a number of human diseases including lysosomal storage diseases (LSD). LSDs are a group of 50 diseases caused predominantly by mutations in lysosomal proteins that result in accumulation of macromolecules within the lysosome. We recently reported that Niemann-Pick type C (NPC) is the first human disease to be associated with defective lysosomal Ca2+ uptake and defective NAADP-mediated lysosomal Ca2+ release. These defects in NPC cells leads to the disruption in endocytosis and subsequent lipid storage that is a feature of this disease. In contrast, Chediak-Higashi Syndrome cells have been reported to have enhanced lysosomal Ca2+ uptake whilst the TRPML1 protein defective in mucolipidosis type IV is believed to function as a Ca2+ channel. In this review we provide a summary of the current knowledge on the role of lysosomal Ca2+ signaling in the pathogenesis of this group of diseases. (C) 2011 Elsevier Ltd. All rights reserved.