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

Authors
 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 
Citation
 EMBO REPORTS, Vol.17(2) : 266-278, 2016 
Journal Title
 EMBO REPORTS 
ISSN
 1469-221X 
Issue Date
2016
MeSH
Animals ; Cells, Cultured ; Excitatory Postsynaptic Potentials ; Exocytosis* ; Glutamic Acid/metabolism ; Lysosomes/metabolism* ; Mice ; Miniature Postsynaptic Potentials ; Mucolipidoses/genetics ; Mucolipidoses/metabolism* ; Neurons/metabolism ; Neurons/physiology ; Niemann-Pick Disease, Type C/genetics ; Niemann-Pick Disease, Type C/metabolism* ; Secretory Vesicles/metabolism* ; Transient Receptor Potential Channels/genetics ; Transient Receptor Potential Channels/metabolism
Keywords
TRPML1 channel ; exocytosis ; lysosomes ; secretory organelles
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.
Full Text
http://embor.embopress.org/content/17/2/266.long
DOI
10.15252/embr.201541542
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Soon Hong(박순홍)
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146313
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