Phosphatidylinositol 3,5-bisphosphate: low abundance, high significance.

Recent studies of the low abundant signaling lipid, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2 ), reveal an intriguingly diverse list of downstream pathways, the intertwined relationship between PI(3,5)P2 and PI5P, as well as links to neurodegenerative diseases. Derived from the structural lipid phosphatidylinositol, PI(3,5)P2 is dynamically generated on multiple cellular compartments where interactions with an increasing list of effectors regulate many cellular pathways. A complex of proteins that includes Fab1/PIKfyve, Vac14, and Fig4/Sac3 mediates the biosynthesis of PI(3,5)P2 , and mutations that disrupt complex function and/or formation cause profound consequences in cells. Surprisingly, mutations in this pathway are linked with neurological diseases, including Charcot-Marie-Tooth syndrome and amyotrophic lateral sclerosis. Future studies of PI(3,5)P2 and PI5P are likely to expand the roles of these lipids in regulation of cellular functions, as well as provide new approaches for treatment of some neurological diseases.