Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina

  1. Domino K Schlegel
  2. Srinivasagan Ramkumar
  3. Johannes von Lintig
  4. Stephan CF Neuhauss  Is a corresponding author
  1. University of Zurich, Switzerland
  2. Case Western Reserve University, United States
  3. Case Western Reserve, United States

Abstract

The RLBP1 gene encodes the 36 kDa cellular retinaldehyde binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod-cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.

Data availability

All data generated or analysed during this study are included in the manuscript. Source data files for all figures have been provided.

Article and author information

Author details

  1. Domino K Schlegel

    University of Zurich, Zürich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  2. Srinivasagan Ramkumar

    Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Johannes von Lintig

    Case Western Reserve, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Stephan CF Neuhauss

    Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland
    For correspondence
    stephan.neuhauss@mls.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9615-480X

Funding

Schweizerische Nationalfonds (31003A_173083)

  • Stephan CF Neuhauss

National Eye Institute (EY028121)

  • Johannes von Lintig

National Eye Institute (EY020551)

  • Johannes von Lintig

Robert und Rosa Pulfer Stiftung

  • Domino K Schlegel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Holding and experimental permits have been granted by the Zurich cantonal veterinary office (TV4206)

Reviewing Editor

  1. Dan Larhammar, Uppsala University, Sweden

Publication history

  1. Preprint posted: June 18, 2021 (view preprint)
  2. Received: June 20, 2021
  3. Accepted: October 20, 2021
  4. Accepted Manuscript published: October 20, 2021 (version 1)
  5. Version of Record published: November 11, 2021 (version 2)

Copyright

© 2021, Schlegel et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 601
    Page views
  • 118
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Domino K Schlegel
  2. Srinivasagan Ramkumar
  3. Johannes von Lintig
  4. Stephan CF Neuhauss
(2021)
Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina
eLife 10:e71473.
https://doi.org/10.7554/eLife.71473

Further reading

    1. Neuroscience
    Arefeh Sherafati et al.
    Research Article Updated

    Cochlear implants are neuroprosthetic devices that can restore hearing in people with severe to profound hearing loss by electrically stimulating the auditory nerve. Because of physical limitations on the precision of this stimulation, the acoustic information delivered by a cochlear implant does not convey the same level of acoustic detail as that conveyed by normal hearing. As a result, speech understanding in listeners with cochlear implants is typically poorer and more effortful than in listeners with normal hearing. The brain networks supporting speech understanding in listeners with cochlear implants are not well understood, partly due to difficulties obtaining functional neuroimaging data in this population. In the current study, we assessed the brain regions supporting spoken word understanding in adult listeners with right unilateral cochlear implants (n=20) and matched controls (n=18) using high-density diffuse optical tomography (HD-DOT), a quiet and non-invasive imaging modality with spatial resolution comparable to that of functional MRI. We found that while listening to spoken words in quiet, listeners with cochlear implants showed greater activity in the left prefrontal cortex than listeners with normal hearing, specifically in a region engaged in a separate spatial working memory task. These results suggest that listeners with cochlear implants require greater cognitive processing during speech understanding than listeners with normal hearing, supported by compensatory recruitment of the left prefrontal cortex.

    1. Neuroscience
    Mohammad Ali Salehinejad et al.
    Research Article Updated

    Sleep strongly affects synaptic strength, making it critical for cognition, especially learning and memory formation. Whether and how sleep deprivation modulates human brain physiology and cognition is not well understood. Here we examined how overnight sleep deprivation vs overnight sufficient sleep affects (a) cortical excitability, measured by transcranial magnetic stimulation, (b) inducibility of long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity via transcranial direct current stimulation (tDCS), and (c) learning, memory, and attention. The results suggest that sleep deprivation upscales cortical excitability due to enhanced glutamate-related cortical facilitation and decreases and/or reverses GABAergic cortical inhibition. Furthermore, tDCS-induced LTP-like plasticity (anodal) abolishes while the inhibitory LTD-like plasticity (cathodal) converts to excitatory LTP-like plasticity under sleep deprivation. This is associated with increased EEG theta oscillations due to sleep pressure. Finally, we show that learning and memory formation, behavioral counterparts of plasticity, and working memory and attention, which rely on cortical excitability, are impaired during sleep deprivation. Our data indicate that upscaled brain excitability and altered plasticity, due to sleep deprivation, are associated with impaired cognitive performance. Besides showing how brain physiology and cognition undergo changes (from neurophysiology to higher-order cognition) under sleep pressure, the findings have implications for variability and optimal application of noninvasive brain stimulation.