Premium
Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
Author(s) -
Fraldi Alessandro,
Annunziata Fabio,
Lombardi Alessia,
Kaiser HermannJosef,
Medina Diego Luis,
Spampanato Carmine,
Fedele Anthony Olind,
Polishchuk Roman,
Sorrentino Nicolina Cristina,
Simons Kai,
Ballabio Andrea
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.237
Subject(s) - endocytic cycle , lipid bilayer fusion , biology , microbiology and biotechnology , lysosome , endocytosis , tfeb , autophagy , mannose 6 phosphate receptor , endosome , lysosomal storage disease , membrane , biochemistry , cell , intracellular , enzyme , apoptosis
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.