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However, the loss of FIG4 decreases PI3,5P<jats:sub>2<\/jats:sub>levels likely due to FIG4's dominant effect in scaffolding a PI3,5P<jats:sub>2<\/jats:sub>synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) recapitulate the pathology in humans with FIG4 deficiency. Using a flow cytometry technique that rapidly quantifies lysosome sizes, we detected an impaired lysosomal fission, but normal fusion, in<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>cells. The fission defect was associated with a robust increase of intralysosomal Ca<jats:sup>2+<\/jats:sup>in<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca<jats:sup>2+<\/jats:sup>efflux of lysosomes because the endogenous ligand of lysosomal Ca<jats:sup>2+<\/jats:sup>channel TRPML1 is PI3,5P<jats:sub>2<\/jats:sub>that is deficient in<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML-SA1. This treatment reduced the intralysosomal Ca<jats:sup>2+<\/jats:sup>level and rescued abnormal lysosomal storage in<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>culture cells and<jats:italic>ex vivo<\/jats:italic>DRGs. Furthermore, we found that the suppressed Ca<jats:sup>2+<\/jats:sup>efflux in<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>culture cells and<jats:italic>Fig4<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mouse brains profoundly downregulated the expression\/activity of dynamin-1, a GTPase known to scissor organelle membranes during fission. This downregulation made dynamin-1 unavailable for lysosomal fission. Together, our study revealed a novel mechanism explaining abnormal lysosomal storage in FIG4 deficiency. Synthetic ligands of the TRPML1 may become a potential therapy against diseases with FIG4 deficiency.<\/jats:p>","DOI":"10.1523\/jneurosci.4442-14.2015","type":"journal-article","created":{"date-parts":[[2015,4,29]],"date-time":"2015-04-29T16:33:04Z","timestamp":1430325184000},"page":"6801-6812","source":"Crossref","is-referenced-by-count":56,"title":["Reactivation of Lysosomal Ca<sup>2+<\/sup>Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient 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