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Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation

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Abstract

D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.

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Acknowledgements

We greatly appreciate the assistance of the members of the Bernard & Shirlee Brown Glaucoma laboratory, especially to Chun-Wei Hsu for technical support. SHT is a Burroughs-Wellcome Program in Biomedical Sciences Fellow, and is also supported by the Charles E. Culpeper-Partnership for Cures 07-CS3, Crowley Research Fund, Schneeweiss Stem Cell Fund, New York State N09G-302, Foundation Fighting Blindness [TA-NMT-0116-0692-COLU] (Owings Mills, MD), TS080017 from US Department of Defense, NIH Grants [P30EY019007, R01EY018213, R01EY024698, R01EY026682, R21AG050437], Research to Prevent Blindness (New York, NY), and Joel Hoffmann Scholarship. CSL is the Homer McK. Rees Scholar. JSP is a BEST2016 awardee (BEST/2016/030, Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana) and his research is supported by a Prometeo Grant (PROMETEO/2016/094; Conselleria de Educación, Investigación, Cultura y Deporte; Generalitat Valenciana) and by internal funds from Universidad Católica de Valencia San Vicente Mártir (2018-128-001). VBM is supported by NIH Grants K08EY020530, R01EY016822, The Doris Duke Charitable Foundation Grant #2013103, and Research to Prevent Blindness (New York, NY); GV is supported by NIH Grants [F30EYE027986 and T32GM007337].

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Author notes

  1. Javier Sancho-Pelluz and Xuan Cui contributed equally to this paper.

Authors and Affiliations

  1. Neurobiología y Neurofisiología, Facultad de Medicina y Odontología, Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain

    Javier Sancho-Pelluz

  2. Jonas Children’s Vision Care and Bernard & Shirlee Brown Glaucoma Laboratory, Departments of Ophthalmology, Pathology, and Cell Biology, Columbia University, New York, NY, 10032, USA

    Javier Sancho-Pelluz, Xuan Cui, Yi-Ting Tsai, Wen-Hsuan Wu, Sally Justus, Chun-Wei Hsu, Karen Sophia Park, Susanne Koch & Stephen H. Tsang

  3. Edward S. Harkness Eye Institute, Columbia University Medical Center, New York Presbyterian Hospital, 635 West 165th St, Box 212, New York, NY, 10032, USA

    Javier Sancho-Pelluz, Xuan Cui, Winston Lee, Yi-Ting Tsai, Wen-Hsuan Wu, Sally Justus, Ilyas Washington, Chun-Wei Hsu, Karen Sophia Park, Susanne Koch & Stephen H. Tsang

  4. Tianjin Medical University Eye Hospital, The College of Optometry, Tianjin Medical University Eye Institute, Tianjin, China

    Xuan Cui

  5. Institute of Human Nutrition and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA

    Yi-Ting Tsai, Wen-Hsuan Wu, Susanne Koch & Stephen H. Tsang

  6. Harvard Medical School, Boston, MA, USA

    Sally Justus

  7. Omics Laboratory, Stanford University, Palo Alto, CA, USA

    Gabriel Velez & Vinit B. Mahajan

  8. Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA

    Gabriel Velez & Vinit B. Mahajan

  9. Medical Scientist Training Program, University of Iowa, Iowa City, IA, USA

    Gabriel Velez

  10. Department of Pediatrics, University of Iowa, Iowa City, IA, USA

    Alexander G. Bassuk

  11. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Chyuan-Sheng Lin & Stephen H. Tsang

Authors
  1. Javier Sancho-Pelluz
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  2. Xuan Cui
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  3. Winston Lee
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  4. Yi-Ting Tsai
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  5. Wen-Hsuan Wu
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  6. Sally Justus
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  7. Ilyas Washington
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  8. Chun-Wei Hsu
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  9. Karen Sophia Park
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  10. Susanne Koch
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  11. Gabriel Velez
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  12. Alexander G. Bassuk
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  14. Chyuan-Sheng Lin
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  15. Stephen H. Tsang
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Contributions

JSP and XC ran most of the experiments: the histology, immunostainings, electron microscopy, ERGs, and glycosilation; WL helped with glycosylation experiments; YT, WS, SK, and CH ran part of the ERG recordings and the western blotting; IW assisted and advised with the experiments; GV, AGB, and VBM created the modeling for D190N rhodopsin and prepared Fig. 1; CSL created the animal model; SHT planned and supervised the experiments; JSP, SJ, and KSP wrote the main document; all authors reviewed the manuscript.

Corresponding author

Correspondence to Stephen H. Tsang.

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Sancho-Pelluz, J., Cui, X., Lee, W. et al. Mechanisms of neurodegeneration in a preclinical autosomal dominant retinitis pigmentosa knock-in model with a RhoD190N mutation. Cell. Mol. Life Sci. 76, 3657–3665 (2019). https://doi.org/10.1007/s00018-019-03090-9

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  • DOI: https://doi.org/10.1007/s00018-019-03090-9

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