1. Biochemistry and Chemical Biology

Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects

  1. Holly Y Chen
  2. Manju Swaroop
  3. Samantha Papal
  4. Anupam Mondal
  5. Hyun Beom Song
  6. Laura Campello
  7. Gregory Tawa
  8. Florian Regent
  9. Hiroko Shimada
  10. Kunio Nagashima
  11. Natalia de Val
  12. Samuel G Jacobson
  13. Wei Zheng
  14. Anand Swaroop  Is a corresponding author
  1. National Eye Institute, United States
  2. National Center for Advancing Translational Sciences, United States
  3. Frederick National Laboratory for Cancer Research, United States
  4. University of Pennsylvania, United States
https://doi.org/10.7554/eLife.83205
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Cite this article
  1. Holly Y Chen
  2. Manju Swaroop
  3. Samantha Papal
  4. Anupam Mondal
  5. Hyun Beom Song
  6. Laura Campello
  7. Gregory Tawa
  8. Florian Regent
  9. Hiroko Shimada
  10. Kunio Nagashima
  11. Natalia de Val
  12. Samuel G Jacobson
  13. Wei Zheng
  14. Anand Swaroop
(2023)
Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects
eLife 12:e83205.
https://doi.org/10.7554/eLife.83205
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Abstract

Ciliopathies manifest from sensory abnormalities to syndromic disorders with multi-organ pathologies, with retinal degeneration a highly penetrant phenotype. Photoreceptor cell death is a major cause of incurable blindness in retinal ciliopathies. To identify drug candidates to maintain photoreceptor survival, we performed an unbiased, high-throughput screening of over 6,000 bioactive small molecules using retinal organoids differentiated from induced pluripotent stem cells (iPSC) of rd16 mouse, which is a model of Leber congenital amaurosis (LCA) type 10 caused by mutations in the cilia-centrosomal gene CEP290. We identified five non-toxic positive hits, including the lead molecule reserpine, which maintained photoreceptor development and survival in rd16 organoids. Reserpine also improved photoreceptors in retinal organoids derived from induced pluripotent stem cells of LCA10 patients and in rd16 mouse retina in vivo. Reserpine-treated patient organoids revealed modulation of signaling pathways related to cell survival/death, metabolism, and proteostasis. Further investigation uncovered dysregulation of autophagy associated with compromised primary cilium biogenesis in patient organoids and rd16 mouse retina. Reserpine partially restored the balance between autophagy and the ubiquitin-proteasome system at least in part by increasing the cargo adaptor p62, resulting in improved primary cilium assembly. Our study identifies effective drug candidates in preclinical studies of CEP290 retinal ciliopathies through cross-species drug discovery using iPSC-derived organoids, highlights the impact of proteostasis in the pathogenesis of ciliopathies, and provides new insights for treatments of retinal neurodegeneration.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. RNA-seq data are available through GEO accession #206959.

The following data sets were generated

Article and author information

Author details

  1. Holly Y Chen

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    Holly Y Chen, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).

  2. Manju Swaroop

    National Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, Rockville, United States
    Competing interests
    Manju Swaroop, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).

  3. Samantha Papal

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    Samantha Papal, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9417-6215

  4. Anupam Mondal

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    Anupam Mondal, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).

  5. Hyun Beom Song

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    No competing interests declared.

  6. Laura Campello

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    No competing interests declared.

  7. Gregory Tawa

    National Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, Rockville, United States
    Competing interests
    Gregory Tawa, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).

  8. Florian Regent

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    No competing interests declared.

  9. Hiroko Shimada

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    Competing interests
    No competing interests declared.

  10. Kunio Nagashima

    Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Frederick, United States
    Competing interests
    No competing interests declared.

  11. Natalia de Val

    Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Frederick, United States
    Competing interests
    No competing interests declared.

  12. Samuel G Jacobson

    Department of Ophthalmology, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.

  13. Wei Zheng

    National Therapeutics for Rare and Neglected Diseases, National Center for Advancing Translational Sciences, Rockville, United States
    Competing interests
    Wei Zheng, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1034-0757

  14. Anand Swaroop

    Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, Bethesda, United States
    For correspondence
    swaroopa@nei.nih.gov
    Competing interests
    Anand Swaroop, Listed as inventor on a patent application related to the small molecules in this study by National Institutes of Health (PCT/US2021/040157).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1975-1141

Funding

National Eye Institute (Z01EY000546)

  • Anand Swaroop

National Eye Institute (Z01EY000450)

  • Anand Swaroop

National Center for Advancing Translational Sciences (ZIATR000018-06)

  • Wei Zheng

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

Ethics

Animal experimentation: All animal procedures were approved by the Animal Care and Use committee of the National Eye Institutes (Animal study protocol NEI-650) and adhered to ARVO Statement for the Use of Animals in Ophthalmic and Vision Research.

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Holly Y Chen
  2. Manju Swaroop
  3. Samantha Papal
  4. Anupam Mondal
  5. Hyun Beom Song
  6. Laura Campello
  7. Gregory Tawa
  8. Florian Regent
  9. Hiroko Shimada
  10. Kunio Nagashima
  11. Natalia de Val
  12. Samuel G Jacobson
  13. Wei Zheng
  14. Anand Swaroop
(2023)
Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects
eLife 12:e83205.
https://doi.org/10.7554/eLife.83205

Share this article

https://doi.org/10.7554/eLife.83205

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Further reading

    1. Medicine

    Sex-specific attenuation of photoreceptor degeneration by reserpine in a rhodopsin P23H rat model of autosomal dominant retinitis pigmentosa

    Hyun Beom Song, Laura Campello ... Anand Swaroop
    Research Advance

    Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Recently, we identified reserpine as a lead molecule for maintaining rod survival in mouse and human retinal organoids as well as in the rd16 mouse, which phenocopy Leber congenital amaurosis caused by mutations in the cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, we show the therapeutic potential of reserpine in a rhodopsin P23H rat model of autosomal dominant RP. At postnatal day (P) 68, when males and females are analyzed together, the reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to the controls with little or no change in scotopic a-wave or cone-derived photopic b-wave. Interestingly, the reserpine-treated female rats display enhanced scotopic a- and b-waves and photopic b-wave responses at P68, along with a better contrast threshold and increased outer nuclear layer thickness. The female rats demonstrate better preservation of both rod and cone photoreceptors following reserpine treatment. Retinal transcriptome analysis reveals sex-specific responses to reserpine, with significant upregulation of phototransduction genes and proteostasis-related pathways, and notably, genes associated with stress response. This study builds upon our previously reported results reaffirming the potential of reserpine for gene-agnostic treatment of IRDs and emphasizes the importance of biological sex in retinal disease research and therapy development.