PUBLICATION
Loss of retinal stem cell reserve and lipofuscin accumulation accelerates cone-rod degeneration and replicates Stargardt disease in abca4b null zebrafish
- Authors
- Pidishetty, D., Damera, S.K., Murugavel, M., Susaimanickam, P.J., Chittajallu, S.N.S.H., Kushawah, G., Sarkar, P., Bharadwaj, S.R., Mishra, R., Mariappan, I.
- ID
- ZDB-PUB-251122-14
- Date
- 2025
- Source
- Scientific Reports : (Journal)
- Registered Authors
- Mariappan, Indumathi, Mishra, Rakesh, Pidishetty, Divya Ashok, Susaimanickam, Praveen Joseph
- Keywords
- Abca4b, CRISPR editing, Retinal degeneration, Retinal stem cells, Stargardt macular degeneration, Zebrafish
- MeSH Terms
-
- ATP-Binding Cassette Transporters*/genetics
- Animals
- CRISPR-Cas Systems
- Cone-Rod Dystrophies*/genetics
- Cone-Rod Dystrophies*/metabolism
- Cone-Rod Dystrophies*/pathology
- Disease Models, Animal
- Gene Knockout Techniques
- Lipofuscin*/metabolism
- Macular Degeneration*/genetics
- Macular Degeneration*/metabolism
- Macular Degeneration*/pathology
- Mutation
- Retina*/metabolism
- Retina*/pathology
- Retinal Cone Photoreceptor Cells/metabolism
- Retinal Cone Photoreceptor Cells/pathology
- Retinal Pigment Epithelium/metabolism
- Retinal Pigment Epithelium/pathology
- Retinal Rod Photoreceptor Cells/metabolism
- Retinal Rod Photoreceptor Cells/pathology
- Stargardt Disease*/genetics
- Stargardt Disease*/metabolism
- Stargardt Disease*/pathology
- Stem Cells*/metabolism
- Stem Cells*/pathology
- Zebrafish/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 41272236 Full text @ Sci. Rep.
Citation
Pidishetty, D., Damera, S.K., Murugavel, M., Susaimanickam, P.J., Chittajallu, S.N.S.H., Kushawah, G., Sarkar, P., Bharadwaj, S.R., Mishra, R., Mariappan, I. (2025) Loss of retinal stem cell reserve and lipofuscin accumulation accelerates cone-rod degeneration and replicates Stargardt disease in abca4b null zebrafish. Scientific Reports. :.
Abstract
Mutations in ABCA4 gene causes Stargardt macular degeneration, which manifests with toxic lipofuscin deposits in the outer retina, gradual atrophy of RPE cells, followed by photoreceptor cell loss. The cone-enriched retina, with macula-like 'area-temporalis' of zebrafish are better models than rodents for studying human macular dystrophies. Here, we generated abca4b knockout zebrafish model using CRISPR/Cas9 editing and evaluated the early and late-stage retinal changes. In adult abca4b-/- mutants, the RPE cells exhibited hyperpigmentation, altered retinomotor behaviour and lipofuscin accumulation, but they remained viable. However, the photoreceptors underwent progressive degeneration, with a sequential loss of blue and UV cones, followed by red and green cones and finally the rod cells. This triggered the chronic activation and early depletion of retinal stem cells at the ciliary marginal zone of mutants and resulted in accelerated outer-retinal degeneration and severe visual defects, despite them retaining the Müller glia-dependant retinal repair potential.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping