Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome

Poppy Datta; Chantal Allamargot; Joseph S Hudson; Emily K Andersen; Sajag Bhattarai; Arlene V Drack; Val C Sheffield; Seongjin Seo

doi:10.1073/pnas.1510111112

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Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome

Journal article

Open access

Peer reviewed

Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome

Poppy Datta, Chantal Allamargot, Joseph S Hudson, Emily K Andersen, Sajag Bhattarai, Arlene V Drack, Val C Sheffield and Seongjin Seo

Proceedings of the National Academy of Sciences - PNAS, Vol.112(32), pp.E4400-E4409

08/11/2015

DOI: 10.1073/pnas.1510111112

PMCID: PMC4538681

PMID: 26216965

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Abstract

Compartmentalization and polarized protein trafficking are essential for many cellular functions. The photoreceptor outer segment (OS) is a sensory compartment specialized for phototransduction, and it shares many features with primary cilia. As expected, mutations disrupting protein trafficking to cilia often disrupt protein trafficking to the OS and cause photoreceptor degeneration. Bardet-Biedl syndrome (BBS) is one of the ciliopathies associated with defective ciliary trafficking and photoreceptor degeneration. However, precise roles of BBS proteins in photoreceptor cells and the underlying mechanisms of photoreceptor degeneration in BBS are not well understood. Here, we show that accumulation of non-OS proteins in the OS underlies photoreceptor degeneration in BBS. Using a newly developed BBS mouse model [Leucine zipper transcription factor-like 1 (Lztfl1)/Bbs17 mutant], isolated OSs, and quantitative proteomics, we determined 138 proteins that are enriched more than threefold in BBS mutant OS. In contrast, only eight proteins showed a more than threefold reduction. We found striking accumulation of Stx3 and Stxbp1/Munc18-1 and loss of polarized localization of Prom1 within the Lztfl1 and Bbs1 mutant OS. Ultrastructural analysis revealed that large vesicles are formed in the BBS OS, disrupting the lamellar structure of the OS. Our findings suggest that accumulation (and consequent sequestration) of non-OS proteins in the OS is likely the primary cause of photoreceptor degeneration in BBS. Our data also suggest that a major function of BBS proteins in photoreceptors is to transport proteins from the OS to the cell body or to prevent entry of non-OS proteins into the OS.

Antibody Specificity

Retinal Photoreceptor Cell Outer Segment - ultrastructure

Reproducibility of Results

Bardet-Biedl Syndrome - metabolism

Cell Separation

Obesity - complications

Mice, Inbred C57BL

Retinal Photoreceptor Cell Outer Segment - metabolism

Ultracentrifugation

Retinal Degeneration - physiopathology

Retinal Photoreceptor Cell Outer Segment - pathology

Retinal Degeneration - metabolism

Blotting, Western

Obesity - pathology

Transcription Factors - metabolism

Animals

Eye Proteins - metabolism

Mice, Mutant Strains

Bardet-Biedl Syndrome - pathology

Proteomics

Retinal Degeneration - pathology

Retinal Degeneration - complications

Details

Title: Subtitle: Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet-Biedl syndrome
Creators: Poppy Datta - Department of Ophthalmology and Visual Sciences, University of Iowa College of Medicine, Iowa City, IA 52242
Chantal Allamargot - Central Microscopy Research Facility, University of Iowa, Iowa City, IA 52242
Joseph S Hudson - Department of Ophthalmology and Visual Sciences, University of Iowa College of Medicine, Iowa City, IA 52242
Emily K Andersen - Department of Ophthalmology and Visual Sciences, University of Iowa College of Medicine, Iowa City, IA 52242
Sajag Bhattarai - Department of Ophthalmology and Visual Sciences, University of Iowa College of Medicine, Iowa City, IA 52242
Arlene V Drack - Department of Ophthalmology and Visual Sciences, University of Iowa College of Medicine, Iowa City, IA 52242
Val C Sheffield - Department of Pediatrics, University of Iowa College of Medicine, Iowa City, IA 52242; Howard Hughes Medical Institute, University of Iowa College of Medicine, Iowa City, IA 52242
Seongjin Seo - Department of Ophthalmology and Visual Sciences, University of Iowa College of Medicine, Iowa City, IA 52242; seongjin-seo@uiowa.edu
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.112(32), pp.E4400-E4409
DOI: 10.1073/pnas.1510111112
PMID: 26216965
PMCID: PMC4538681
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: United States
Grant note: R01 EY011298 / NEI NIH HHS R01 NS083543 / NINDS NIH HHS R01 EY022616 / NEI NIH HHS Howard Hughes Medical Institute R01 EY017168 / NEI NIH HHS
Language: English
Date published: 08/11/2015
Academic Unit: Stead Family Department of Pediatrics; Core Research Facilities; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9983979994102771

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