Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV

Soonhong Park, Malini Ahuja, Min Seuk Kim, G. Cristina Brailoiu, Archana Jha, Mei Zeng, Maryna Baydyuk, Ling Gang Wu, Christopher A. Wassif, Forbes D. Porter, Patricia M. Zerfas, Michael A. Eckhaus, Eugen Brailoiu, Dong Min Shin, Shmuel Muallem

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells' functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re-expression of TRPML1 in neurons. These features were not observed in Niemann-Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV.

Original languageEnglish
Pages (from-to)266-278
Number of pages13
JournalEMBO Reports
Volume17
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV'. Together they form a unique fingerprint.

  • Cite this

    Park, S., Ahuja, M., Kim, M. S., Brailoiu, G. C., Jha, A., Zeng, M., Baydyuk, M., Wu, L. G., Wassif, C. A., Porter, F. D., Zerfas, P. M., Eckhaus, M. A., Brailoiu, E., Shin, D. M., & Muallem, S. (2016). Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV. EMBO Reports, 17(2), 266-278. https://doi.org/10.15252/embr.201541542