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.
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD, USA Department of Oral Biology, BK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Soonhong
authors.initials: S
authors.lastname: Park
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD, USA.
authors.forename: Malini
authors.initials: M
authors.lastname: Ahuja
authors.affiliation: Department of Oral Physiology, School of Dentistry, Wonkwang University, Iksan City, Korea.
authors.forename: Min Seuk
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Sciences, Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: G Cristina
authors.initials: GC
authors.lastname: Brailoiu
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Jha
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Zeng
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Maryna
authors.initials: M
authors.lastname: Baydyuk
authors.affiliation: National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
authors.forename: Ling-Gang
authors.initials: LG
authors.lastname: Wu
authors.affiliation: Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
authors.affiliation: Diagnostic and Research Services Branch, Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Zerfas
authors.affiliation: Diagnostic and Research Services Branch, Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eckhaus
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Eugen
authors.initials: E
authors.lastname: Brailoiu
authors.affiliation: Department of Oral Biology, BK 21 PLUS Project, Yonsei University College of Dentistry, Seoul, Korea dmshin@yuhs.ac shmuel.muallem@nih.gov.
authors.forename: Dong Min
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Epithelial Signaling and Transport Section, Molecular Physiology and Therapeutics Branch, NIDCR, NIH, Bethesda, MD, USA dmshin@yuhs.ac shmuel.muallem@nih.gov.
authors.forename: Shmuel
authors.initials: S
authors.lastname: Muallem
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D005089:Exocytosis; D018698:Glutamic Acid / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism
chemical_list: C512321:Mcoln1 protein, mouse; D050051:Transient Receptor Potential Channels; D018698:Glutamic Acid
keywords: TRPML1 channel; exocytosis; lysosomes; secretory organelles