title: Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders.
abstract: The function of lysosomes relies on the ability of the lysosomal membrane to fuse with several target membranes in the cell. It is known that in lysosomal storage disorders (LSDs), lysosomal accumulation of several types of substrates is associated with lysosomal dysfunction and impairment of endocytic membrane traffic. By analysing cells from two severe neurodegenerative LSDs, we observed that cholesterol abnormally accumulates in the endolysosomal membrane of LSD cells, thereby reducing the ability of lysosomes to efficiently fuse with endocytic and autophagic vesicles. Furthermore, we discovered that soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNAREs), which are key components of the cellular membrane fusion machinery are aberrantly sequestered in cholesterol-enriched regions of LSD endolysosomal membranes. This abnormal spatial organization locks SNAREs in complexes and impairs their sorting and recycling. Importantly, reducing membrane cholesterol levels in LSD cells restores normal SNARE function and efficient lysosomal fusion. Our results support a model by which cholesterol abnormalities determine lysosomal dysfunction and endocytic traffic jam in LSDs by impairing the membrane fusion machinery, thus suggesting new therapeutic targets for the treatment of these disorders.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
authors.forename: Fabio
authors.initials: F
authors.lastname: Annunziata
authors.forename: Alessia
authors.initials: A
authors.lastname: Lombardi
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Kaiser
authors.forename: Diego Luis
authors.initials: DL
authors.lastname: Medina
authors.forename: Carmine
authors.initials: C
authors.lastname: Spampanato
authors.forename: Anthony Olind
authors.initials: AO
authors.lastname: Fedele
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.forename: Nicolina Cristina
authors.initials: NC
authors.lastname: Sorrentino
authors.forename: Kai
authors.initials: K
authors.lastname: Simons
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D016464:Lysosomal Storage Diseases / Q000378:metabolism* / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008561:Membrane Fusion / Q000502:physiology*; D051379:Mice; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050600:SNARE Proteins / Q000378:metabolism*; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D002784:Cholesterol; D066246:ErbB Receptors; D051907:Lysosomal Membrane Proteins; D010743:Phospholipids; D012333:RNA, Messenger; D050600:SNARE Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C541485:EGFR protein, mouse