Reactivation of lysosomal Ca2+ efflux rescues abnormal lysosomal storage in FIG4-deficient cells

Jianlong Zou, Bo Hu, Sezgi Arpag, Qing Yan, Audra Hamilton, Yuan Shan Zeng, Carlos G. Vanoye, Jun Li

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


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 PI3,5P2 levels likely due to FIG4's dominant effect in scaffolding a PI3,5P2 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 (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, in Fig4−/− cells. The fission defect was associated with a robust increase of intralysosomal Ca2+ in Fig4−/− 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 PI3,5P2 that is deficient in Fig4−/− 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 in Fig4−/− culture cells and ex vivo DRGs. Furthermore, we found that the suppressed Ca2+ efflux in Fig4−/− culture cells and Fig4−/− 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.

Original languageEnglish (US)
Pages (from-to)6801-6812
Number of pages12
JournalJournal of Neuroscience
Issue number17
StatePublished - Apr 29 2015


  • Charcot-Marie-Tooth disease
  • Lysosomal storage
  • ML-SA1
  • Membrane trafficking
  • Neurodegeneration
  • TRPML1

ASJC Scopus subject areas

  • Neuroscience(all)


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