Late Endosomal Cholesterol Accumulation Leads to Impaired Intra-Endosomal Trafficking

Sobo, Komla, Le Blanc, Isabelle, Luyet, Pierre-Philippe, Fivaz, Marc, Ferguson, Charles, Parton, Robert G., Gruenberg, Jean and van der Goot, F. Gisou (2007) Late Endosomal Cholesterol Accumulation Leads to Impaired Intra-Endosomal Trafficking. PLoS One, 2 9: e851-701. doi:10.1371/journal.pone.0000851


Author Sobo, Komla
Le Blanc, Isabelle
Luyet, Pierre-Philippe
Fivaz, Marc
Ferguson, Charles
Parton, Robert G.
Gruenberg, Jean
van der Goot, F. Gisou
Title Late Endosomal Cholesterol Accumulation Leads to Impaired Intra-Endosomal Trafficking
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2007-09-01
Year available 2007
Sub-type Article (original research)
DOI 10.1371/journal.pone.0000851
Open Access Status DOI
Volume 2
Issue 9
Start page e851
End page 701
Total pages 11
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Abstract The retromer complex is a highly conserved membrane trafficking assembly composed of three proteins - Vps26, Vps29 and Vps35 - that were identified over a decade ago in Saccharomyces cerevisiae (S. cerevisiae). Initially, mammalian retromer was shown to sort transmembrane proteins from the endosome to the trans-Golgi network (TGN), though recent work has identified a critical role for retromer in multiple trafficking pathways, including recycling to the plasma membrane and regulation of cell polarity. In recent years, genetic, cellular, pharmacological and animal model studies have identified retromer and its interacting proteins as being linked to familial forms of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD). Here, this commentary will summarize recently identified point mutations in retromer linked to PD, and explore the molecular functions of retromer that may be relevant to disease progression.
Formatted abstract
Background.
Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics.

Methodology/Principal Findings.
Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated. Strikingly, we observed a 2-3 fold increase in the size of the compartment. Most importantly, properties and dynamics of late endosomal intralumenal vesicles were altered as revealed by reduced late endosomal vacuolation induced by the mutant pore-forming toxin ASSP, reduced intoxication by the anthrax lethal toxin and inhibition of infection by the Vesicular Stomatitis Virus.

Conclusions/Significance.

These results suggest that back fusion of intralumenal vesicles with the limiting membrane of late endosomes is dramatically perturbed upon cholesterol accumulation.
Keyword Cathepsin D
Parkinson's disease
Vps35 p.D620N
Vps35 p.R524W
endosome
retromer
sorting nexin
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: ERA 2012 Admin Only
Institute for Molecular Bioscience - Publications
 
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