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

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

Research output: Contribution to journalArticle

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)266-278
Number of pages13
JournalEMBO Reports
Volume17
Issue number2
DOIs
Publication statusPublished - 2016 Feb 1

Fingerprint

Mucolipidoses
Lysosomal Storage Diseases
Exocytosis
Lysosomes
Organelles
Neurons
Fusion reactions
Glutamic Acid
Membranes
Mutation
Synaptic Vesicles
Secretory Vesicles

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

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. / Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV. In: EMBO Reports. 2016 ; Vol. 17, No. 2. pp. 266-278.
@article{a299084a7f15447493adb4f1e9948631,
title = "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.",
author = "Soonhong Park and Malini Ahuja and Kim, {Min Seuk} and Brailoiu, {G. Cristina} and Archana Jha and Mei Zeng and Maryna Baydyuk and Wu, {Ling Gang} and Wassif, {Christopher A.} and Porter, {Forbes D.} and Zerfas, {Patricia M.} and Eckhaus, {Michael A.} and Eugen Brailoiu and Shin, {Dong Min} and Shmuel Muallem",
year = "2016",
month = "2",
day = "1",
doi = "10.15252/embr.201541542",
language = "English",
volume = "17",
pages = "266--278",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "2",

}

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 2016, 'Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV', EMBO Reports, vol. 17, no. 2, pp. 266-278. https://doi.org/10.15252/embr.201541542

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

In: EMBO Reports, Vol. 17, No. 2, 01.02.2016, p. 266-278.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV

AU - Park, Soonhong

AU - Ahuja, Malini

AU - Kim, Min Seuk

AU - Brailoiu, G. Cristina

AU - Jha, Archana

AU - Zeng, Mei

AU - Baydyuk, Maryna

AU - Wu, Ling Gang

AU - Wassif, Christopher A.

AU - Porter, Forbes D.

AU - Zerfas, Patricia M.

AU - Eckhaus, Michael A.

AU - Brailoiu, Eugen

AU - Shin, Dong Min

AU - Muallem, Shmuel

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84957434829&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84957434829&partnerID=8YFLogxK

U2 - 10.15252/embr.201541542

DO - 10.15252/embr.201541542

M3 - Article

C2 - 26682800

AN - SCOPUS:84957434829

VL - 17

SP - 266

EP - 278

JO - EMBO Reports

JF - EMBO Reports

SN - 1469-221X

IS - 2

ER -