Retinal alterations resemble brain pathology in a rat model of Parkinson’s disease induced by intranigral infusion of α-synuclein oligomers

Parkinson’s disease (PD) is a debilitating neurodegenerative synucleinopathy, characterized by dopaminergic degeneration, pathological deposition of alpha-synuclein (α-Syn), and neuroinflammation in both motor regions of the midbrain and non-motor areas of the cortex. Despite its motor-centric characterization, visual disturbances such as hallucinations, diplopia, altered contrast sensitivity and retinal abnormalities are well-documented non-motor changes of PD. While this evidence points to neuropathological processes in PD that extend beyond the brain, the neuropathological basis of retinal dysfunction and the role of α-Syn remain poorly investigated. Given the central neuropathological role of α-Syn in the PD brain, we assessed whether the retina is affected in a translational rat model of PD based on the intranigral bilateral infusion of toxic oligomers of human α-Synuclein (H-α-SynOs). Rats were stereotaxically injected with H-α-SynOs or PBS (Vehicle) into the substantia nigra pars compacta (SNpc) and sacrificed 3 months post-infusion. Thereafter, several retinal tissue pathological parameters, along with the expression patterns of selected miRNAs and inflammatory markers, were assessed. The retina of rats infused with H-α-SynOs exhibited high levels of phosphorylated-α-Syn (p-α-Syn), along with a significant decrease of tyrosine hydroxylase (TH) expression, reflecting dopaminergic neuron disfunction. Analysis of PD-associated miRNAs in the retina also revealed heightened levels of miR-384-5p, which inversely correlated with the expression of its predicted molecular target, SIRT1, in rats infused with H-α-SynOs. Consistently, H-α-SynOs infusion induced a widespread activation of retinal astrocytes and microglial markers, associated with a heightened proinflammatory cytokine signaling downstream of TLR4/NFκB. Collectively, our data reveal that H-α-SynOs extend their neuropathological effects to retinal damage, reinforcing our rodent model ability to recapitulate PD pathology in both brain and retina. This study underscores the robustness of this preclinical model and its value as translational system for testing proactive interventions targeting PD-related pathology. (Figure presented.)