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

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 Rep

journal_title

EMBO reports

authors

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 S

doi

10.15252/embr.201541542

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

266-78

issue

2

eissn

1469-221X

issn

1469-3178

pii

embr.201541542

journal_volume

17

pub_type

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