Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations
Abstract PRLΔE1, a retina-specific isoform of prolactin, is expressed in multiple and diverse forms of canine inherited retinal degeneration (IRD). We find that while PRLΔE1 expression in rods is not associated with the initial phase of disease characterized by acute photoreceptor cell death, it is...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-09-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07070-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849333969342955520 |
|---|---|
| author | Raghavi Sudharsan Jennifer Kwok Malgorzata Swider Alexander Sumaroka Gustavo D. Aguirre Artur V. Cideciyan William A. Beltran |
| author_facet | Raghavi Sudharsan Jennifer Kwok Malgorzata Swider Alexander Sumaroka Gustavo D. Aguirre Artur V. Cideciyan William A. Beltran |
| author_sort | Raghavi Sudharsan |
| collection | DOAJ |
| description | Abstract PRLΔE1, a retina-specific isoform of prolactin, is expressed in multiple and diverse forms of canine inherited retinal degeneration (IRD). We find that while PRLΔE1 expression in rods is not associated with the initial phase of disease characterized by acute photoreceptor cell death, it is associated with the protracted phase of slow cell loss. Restoration of photoreceptors to a healthy state by gene-specific replacement therapy of individual IRDs successfully suppresses PRLΔE1 expression. Moreover, short-term PRLΔE1 silencing using shRNA results in preservation of outer nuclear layer thickness, suggesting PRLΔE1 drives retinal disease. However, longer-term observations reveal off-target toxic effects of the PRLΔE1 shRNA, precluding determination of its full therapeutic potential. Future research efforts aimed at enhancing the safety and specificity of PRLΔE1-targeting strategies may identify a potential universal intervention strategy for sustaining photoreceptors during the prolonged phase of multiple IRDs. |
| format | Article |
| id | doaj-art-e37984bba17c4ae580d9b5b917c7b0d9 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e37984bba17c4ae580d9b5b917c7b0d92025-08-20T03:45:41ZengNature Publishing GroupCell Death and Disease2041-48892024-09-0115911010.1038/s41419-024-07070-1Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerationsRaghavi Sudharsan0Jennifer Kwok1Malgorzata Swider2Alexander Sumaroka3Gustavo D. Aguirre4Artur V. Cideciyan5William A. Beltran6Division of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of PennsylvaniaDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of PennsylvaniaCenter for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of MedicineCenter for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of MedicineDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of PennsylvaniaCenter for Hereditary Retinal Degenerations, Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of MedicineDivision of Experimental Retinal Therapies, Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of PennsylvaniaAbstract PRLΔE1, a retina-specific isoform of prolactin, is expressed in multiple and diverse forms of canine inherited retinal degeneration (IRD). We find that while PRLΔE1 expression in rods is not associated with the initial phase of disease characterized by acute photoreceptor cell death, it is associated with the protracted phase of slow cell loss. Restoration of photoreceptors to a healthy state by gene-specific replacement therapy of individual IRDs successfully suppresses PRLΔE1 expression. Moreover, short-term PRLΔE1 silencing using shRNA results in preservation of outer nuclear layer thickness, suggesting PRLΔE1 drives retinal disease. However, longer-term observations reveal off-target toxic effects of the PRLΔE1 shRNA, precluding determination of its full therapeutic potential. Future research efforts aimed at enhancing the safety and specificity of PRLΔE1-targeting strategies may identify a potential universal intervention strategy for sustaining photoreceptors during the prolonged phase of multiple IRDs.https://doi.org/10.1038/s41419-024-07070-1 |
| spellingShingle | Raghavi Sudharsan Jennifer Kwok Malgorzata Swider Alexander Sumaroka Gustavo D. Aguirre Artur V. Cideciyan William A. Beltran Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations Cell Death and Disease |
| title | Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations |
| title_full | Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations |
| title_fullStr | Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations |
| title_full_unstemmed | Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations |
| title_short | Retinal prolactin isoform PRLΔE1 sustains rod disease in inherited retinal degenerations |
| title_sort | retinal prolactin isoform prlδe1 sustains rod disease in inherited retinal degenerations |
| url | https://doi.org/10.1038/s41419-024-07070-1 |
| work_keys_str_mv | AT raghavisudharsan retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations AT jenniferkwok retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations AT malgorzataswider retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations AT alexandersumaroka retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations AT gustavodaguirre retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations AT arturvcideciyan retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations AT williamabeltran retinalprolactinisoformprlde1sustainsroddiseaseininheritedretinaldegenerations |