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Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
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Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
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Journal Article
Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders
2010
Overview
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.
Lysosomal storage disorders involve lysosomal dysfunction and defective endocytic membrane trafficking. However, the underlying mechanism(s) remain largely unclear. In this study, Andrea Ballabio
et al.
reveal that cholesterol accumulates in the endolysosomal system of LSD cells and interferes with the activity of the lysosomal SNARE membrane fusion machinery
Publisher
John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ Animals
/ EMBO20
/ EMBO24
/ Embryo, Mammalian - cytology
/ Embryo, Mammalian - metabolism
/ Fluorescent Antibody Technique
/ Lysosomal Membrane Proteins - genetics
/ Lysosomal Membrane Proteins - metabolism
/ Lysosomal Storage Diseases - metabolism
/ Lysosomal Storage Diseases - pathology
/ lysosome
/ Membrane Fusion - physiology
/ Mice
/ Reverse Transcriptase Polymerase Chain Reaction
/ SNAREs
