Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders

Alessandro Fraldi, Fabio Annunziata, Alessia Lombardi, Hermann Josef Kaiser, Diego Luis Medina, Carmine Spampanato, Anthony Fedele, Roman Polishchuk, Nicolina Cristina Sorrentino, Kai Simons, Andrea Ballabio

Research output: Contribution to journalArticlepeer-review

154 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3607-3620
Number of pages14
JournalEMBO Journal
Volume29
Issue number21
DOIs
Publication statusPublished or Issued - 3 Nov 2010

Keywords

  • SNAREs
  • autophagy
  • lysosomal fusion
  • lysosomal storage disorders
  • lysosome

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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