Abstract
Parkinson’s disease (PD) affects motor and non-motor systems; however, retinal changes and their molecular basis are not well understood. Using a transgenic mouse model overexpressing A53T-mutant human α-synuclein, we examined retinal function, structure, and proteomics at 6- and 16 months. Early retinal dysfunction was detected by a reduction in scotopic oscillatory potential amplitudes on electroretinography. Optical coherence tomography showed early thinning of the retinal nerve fiber layer/ganglion cell layer, and photoreceptor layer, accompanied by thickening of the inner plexiform layer. Phosphorylated α-synuclein accumulation, increased glial fibrillary acidic protein, and loss of the ribbon synapse protein CtBP2 were observed. Proteomic profiling revealed stage-dependent alterations involving α-synuclein, oxidative stress markers, and crystallins. Network analysis showed progression from α-synuclein-associated disruption to inflammation and metabolic remodeling. These results highlight retinal alterations as early indicators of PD neurodegeneration and provide mechanistic insights into the molecular events that precede neuronal loss.
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Mass spectrometry proteomic data were deposited in the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD066087.
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Acknowledgements
This study was supported by the Nano-Material Technology Development Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (NRF-2022M3H4A4085936); the Korea Mouse Phenotyping Project (RS-2024-00400118) from the Ministry of Science and ICT through the National Research Foundation. The funding bodies had no role in the design of the study, collection, analysis, and interpretation of data, or in writing the manuscript.
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C.-E.M. and S.J.L. contributed equally to this study. C.-E.M. contributed to the conceptualization, methodology, formal analysis, investigation, data curation, original draft writing, and visualization. S.J.L. contributed to original draft writing, review, and editing. H.S., H.K., J.-K.L., and H.J.K. were involved in the investigation. H.S.K. and I.H.M. were involved in writing. S.S.K., H.K.L., K.Y.S., and S.-R.C. contributed to supervision and project administration. Y.W.J. contributed to conceptualization, writing, supervision, and project administration. All the authors have read and approved the final version of the manuscript.
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Moon, CE., Lee, S.J., Shin, H. et al. Early retinal synaptic dysfunction and proteomic remodeling precede neurodegeneration in a Parkinson’s disease model. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01261-7
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DOI: https://doi.org/10.1038/s41531-026-01261-7
