Reactivation of Lysosomal Ca2+Efflux Rescues Abnormal Lysosomal Storage in FIG4-Deficient Cells

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Abstract
Loss of function of FIG4 leads to Charcot-Marie-Tooth disease Type 4J, Yunis-Varon syndrome, or an epilepsy syndrome. FIG4 is a phosphatase with its catalytic specificity toward 5′-phosphate of phosphatidylinositol-3,5-diphosphate (PI3,5P2). However, the loss of FIG4 decreases PI3,5P2levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2synthetic protein complex. At the cellular level, all these diseases share similar pathology with abnormal lysosomal storage and neuronal degeneration. Mice with no FIG4 expression (Fig4−/−) 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, inFig4−/−cells. The fission defect was associated with a robust increase of intralysosomal Ca2+inFig4−/−cells, including FIG4-deficient neurons. This finding was consistent with a suppressed Ca2+efflux of lysosomes because the endogenous ligand of lysosomal Ca2+channel TRPML1 is PI3,5P2that is deficient inFig4−/−cells. We reactivated the TRPML1 channels by application of TRPML1 synthetic ligand, ML-SA1. This treatment reduced the intralysosomal Ca2+level and rescued abnormal lysosomal storage inFig4−/−culture cells andex vivoDRGs. Furthermore, we found that the suppressed Ca2+efflux inFig4−/−culture cells andFig4−/−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.

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