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Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV
Author(s) -
Park Soonhong,
Ahuja Malini,
Kim Min Seuk,
Brailoiu G Cristina,
Jha Archana,
Zeng Mei,
Baydyuk Maryna,
Wu LingGang,
Wassif Christopher A,
Porter Forbes D,
Zerfas Patricia M,
Eckhaus Michael A,
Brailoiu Eugen,
Shin Dong Min,
Muallem Shmuel
Publication year - 2016
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201541542
Subject(s) - exocytosis , mucolipidosis , organelle , microbiology and biotechnology , lysosomal storage disease , lysosome , chemistry , biology , biochemistry , secretion , enzyme
Mutations in TRPML 1 cause the lysosomal storage disease mucolipidosis type IV ( MLIV ). The role of TRPML 1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML 1 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 mEPSC s, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re‐expression of TRPML 1 in neurons. These features were not observed in Niemann–Pick type C1. These findings suggest that TRPML 1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV .