RETINAL FUNCTIONAL AND MOLECULAR ALTERATIONS ACROSS DISEASE STAGES IN A PARKINSON’S DISEASE MOUSE MODEL

Parkinson’s disease (PD) involves both motor and non-motor systems, yet the progression of retinal pathology and its molecular basis remain unclear. We investigated retinal function, structure, and proteomics using an A53T-mutant human α-synuclein transgenic mouse model at 6 and 16 months.
Electroretinography (ERG) revealed early functional impairment, evidenced by reduced scotopic oscillatory potential amplitudes at 6 months. Optical coherence tomography (OCT) showed early thinning of the retinal nerve fiber/ganglion cell and photoreceptor layers, accompanied by inner plexiform layer (IPL) thickening. These changes coincided with phosphorylated α-synuclein accumulation, increased GFAP expression, and loss of the ribbon synapse protein CtBP2.
Quantitative proteomics identified stage-dependent alterations in α-synuclein, oxidative stress markers, and crystallins. Network analysis indicated a pathological transition from α-synuclein-associated disruption at 6 months toward chronic inflammation and metabolic remodeling at 16 months. To strengthen tissue-level interpretation, we prioritized candidates involved in interneuron-related signaling (relevant to IPL circuitry) and myelin/axon processes (e.g., PLP1). Immunofluorescence analyses in retina are performed to evaluate cell-type– and layer-specific alterations of these candidates.
Our findings demonstrate that retinal functional and molecular remodeling occur well before overt neurodegeneration. These results position the retina as a sensitive window into early PD pathology and provide mechanistic insights into molecular events preceding neuronal loss, highlighting candidate biomarkers and therapeutic targets.