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.
journal_name
EMBO Repjournal_title
EMBO reportsauthors
Park S,Ahuja M,Kim MS,Brailoiu GC,Jha A,Zeng M,Baydyuk M,Wu LG,Wassif CA,Porter FD,Zerfas PM,Eckhaus MA,Brailoiu E,Shin DM,Muallem Sdoi
10.15252/embr.201541542subject
Has Abstractpub_date
2016-02-01 00:00:00pages
266-78issue
2eissn
1469-221Xissn
1469-3178pii
embr.201541542journal_volume
17pub_type
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