Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV. (18th December 2015)

• Record Type: Journal Article
• Authors: Park, Soonhong; Ahuja, Malini; Kim, Min Seuk; Brailoiu, G Cristina; Jha, Archana; Zeng, Mei; Baydyuk, Maryna; Wu, Ling‐Gang; Wassif, Christopher A; Porter, Forbes D; Zerfas, Patricia M; Eckhaus, Michael A; Brailoiu, Eugen; Shin, Dong Min; Muallem, Shmuel
• Is Part Of: EMBO reports. Volume 17:Number 2(2016:Feb.)
• Page Start: 266
• Page End: 278
• Publication Date: 2015-12-18
• Subjects: exocytosis -- lysosomes -- secretory organelles -- TRPML1 channel; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201541542
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: Deletion of TRPML1, the channel mutated in mucolipidosis type 4, increases the size of secretory organelles to enhance regulated exocytosis, which may account for part of the pathology in the disease. Deletion of TRPML1 increases secretory organelle size by fusion with lysosomes. The fusion increases all forms of regulated exocytosis. The enhanced exocytosis can account in part for the pathology in mucolipidosis type 4. Abstract : Deletion of TRPML1, the channel mutated in mucolipidosis type 4, increases the size of secretory organelles to enhance regulated exocytosis, which may account for part of the pathology in the disease.