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

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.

SUBMITTER: Masek M

PROVIDER: S-EPMC8917222 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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

Masek Markus M Etard Christelle C Hofmann Claudia C Hülsmeier Andreas J AJ Zang Jingjing J Takamiya Masanari M Gesemann Matthias M Neuhauss Stephan C F SCF Hornemann Thorsten T Strähle Uwe U Bachmann-Gagescu Ruxandra R

Nature communications 20220311 1

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 ...[more]

PMID: 35277505

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Project description:<h4>Summary</h4>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 new 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 isolated OSs show that Bbs1 is required for BBSome-entry into OSs 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 new role for Bbs1/BBSome in OS lipid homeostasis and suggest a new pathomechanism underlying retinal degeneration in BBS. Data availability:The proteomic data generated in this study have been deposited in PRIDE repository under accession code <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD026646' rel='noopener noreferrer' target='_blank'>PXD026646</a> for the OS proteome and <a href='https://www.ebi.ac.uk/pride/archive/projects/PXD030522' rel='noopener noreferrer' target='_blank'>PXD030522</a> for the whole eye lysate proteome [<a href='https://www.ebi.ac.uk/pride' rel='noopener noreferrer' target='_blank'>https://www.ebi.ac.uk/pride</a>].The RNAseq data generated in this study have been deposited in the SRA repository under the BioProject accession number PRJNA789116 [<a href='https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA789116' rel='noopener noreferrer' target='_blank'>https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA789116</a>].

Project description:C8ORF37 is a causative gene for three different clinical forms of incurable retinal degeneration. However, the completely unknown function of C8ORF37 limits our understanding of the pathogenicity of C8ORF37 mutations. Here, we performed a comprehensive phenotypic characterization of a C8orf37 KO mouse line, generated using CRISPR/Cas9 technology. Both C8orf37 KO male and female mice exhibited progressive and simultaneous degeneration of rod and cone photoreceptors but no non-ocular phenotypes. The major ultrastructural feature of C8orf37 KO photoreceptors was massive disorganization of the outer segment (OS) membrane discs starting from the onset of disc morphogenesis during development. At the molecular level, the amounts of multiple OS-specific membrane proteins, including proteins involved in membrane disc organization, were reduced, although these proteins were targeted normally to the OS. Considering the distribution of C8ORF37 throughout the photoreceptor cell body, the normal structure of the KO photoreceptor connecting cilium, and the absence of defects in other ciliary organs of the KO mice, our findings do not support the previous notion that C8ORF37 was a ciliary protein. Because C8ORF37 is absent in the photoreceptor OS, C8ORF37 may participate in the secretory pathway of OS membrane proteins in the photoreceptor cell body and thus maintain the homeostasis of these proteins. This study established a valid animal model for future therapeutic studies of C8ORF37-associated retinal degeneration. This study also shed new light on the role of C8ORF37 in photoreceptors and on the pathogenic mechanism underlying retinal degeneration caused by C8ORF37 mutations.SIGNIFICANCE STATEMENT Inherited retinal degeneration is a group of incurable conditions with poorly understood underlying molecular mechanisms. We investigated C8ORF37, a causative gene for three retinal degenerative conditions: retinitis pigmentosa, cone-rod dystrophy, and Bardet-Biedl syndrome. C8ORF37 encodes a protein with no known functional domains and thus its biological function is unpredictable. We knocked out the C8ORF37 ortholog in mice, which resulted in a retinal phenotype similar to that observed in patients. We further demonstrated that C8ORF37 is required for photoreceptor outer segment disc formation and alignment, a process that is critical for photoreceptor function and survival. This study advances our understanding of the pathogenesis of retinal degeneration and establishes a valuable mouse model for future therapeutic development.

Dataset Information

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

Publications

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

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