Early retinal synaptic dysfunction and proteomic remodeling precede neurodegeneration in a Parkinson's disease model

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 alpha-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 alpha-synuclein accumulation, increased glial fibrillary acidic protein, and loss of the ribbon synapse protein CtBP2 were observed. Proteomic profiling revealed stage-dependent alterations involving alpha-synuclein, oxidative stress markers, and crystallins. Network analysis showed progression from alpha-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.