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Loss of the Bardet-Biedl protein Bbs1 alters photoreceptor outer segment protein and lipid composition


Masek, Markus; Etard, Christelle; Hofmann, Claudia; Hülsmeier, Andreas J; Zang, Jingjing; Takamiya, Masanari; Gesemann, Matthias; Neuhauss, Stephan C F; Hornemann, Thorsten; Strähle, Uwe; Bachmann-Gagescu, Ruxandra (2022). Loss of the Bardet-Biedl protein Bbs1 alters photoreceptor outer segment protein and lipid composition. Nature Communications, 13:1282.

Abstract

Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on samples enriched for isolated OSs show that Bbs1 is required for BBSome-complex stability and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a role for Bbs1/BBSome in OS lipid homeostasis, suggesting a pathomechanism underlying retinal degeneration in BBS.

Abstract

Primary cilia are key sensory organelles whose dysfunction leads to ciliopathy disorders such as Bardet-Biedl syndrome (BBS). Retinal degeneration is common in ciliopathies, since the outer segments (OSs) of photoreceptors are highly specialized primary cilia. BBS1, encoded by the most commonly mutated BBS-associated gene, is part of the BBSome protein complex. Using a bbs1 zebrafish mutant, we show that retinal development and photoreceptor differentiation are unaffected by Bbs1-loss, supported by an initially unaffected transcriptome. Quantitative proteomics and lipidomics on samples enriched for isolated OSs show that Bbs1 is required for BBSome-complex stability and that Bbs1-loss leads to accumulation of membrane-associated proteins in OSs, with enrichment in proteins involved in lipid homeostasis. Disruption of the tightly regulated OS lipid composition with increased OS cholesterol content are paralleled by early functional visual deficits, which precede progressive OS morphological anomalies. Our findings identify a role for Bbs1/BBSome in OS lipid homeostasis, suggesting a pathomechanism underlying retinal degeneration in BBS.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Uncontrolled Keywords:General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry
Language:English
Date:1 December 2022
Deposited On:17 Mar 2022 08:47
Last Modified:27 Apr 2024 01:36
Publisher:Nature Publishing Group
ISSN:2041-1723
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/s41467-022-28982-6
PubMed ID:35277505
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_173083
  • : Project TitleGenetic Analysis of Vertebrate Vision
  • : FunderSNSF
  • : Grant ID31003A_179371
  • : Project TitleKeep it in Balance - the cellular regulation of sphingolipid homeostasis
  • : FunderSNSF
  • : Grant IDPP00P3_170681
  • : Project TitleUnderstanding the molecular mechanisms underlying phenotypic variability in ciliopathies
  • : FunderHelmoltz Association BioInterfaces program
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)