Abstract
Purpose :
Loss of substantia nigral dopaminergic cells and alpha-synuclein (α-syn) rich intraneuronal deposits are key hallmarks of Parkinson’s disease (PD). This study aims to evaluate retinal changes in a well-characterised model of α-syn overexpression, and whether acute levodopa (L-DOPA) treatment has any restorative effects on the retina.
Methods :
Human A53T (hA53T) α-syn expressing mice, and wildtype (WT) littermates (6 months old) were intraperitoneally given L-DOPA or vehicle saline (n=11-18 per group). In vivo retinal function (dark-adapted full field electroretinogram, ERG) and structure (optical coherence tomography, OCT) were recorded before and after drug treatment (over 30 minutes). Photoreceptor (a-wave) and bipolar cell (b-wave) amplitudes and retinal layer thickness profiles were analysed. Ex vivo retinal protein assessment (immunohistochemistry, IHC; Western Blot, WB) was also conducted. Two-way ANOVAs with Sidak’s correction for multiple comparisons were used to compare groups.
Results :
Photoreceptor and bipolar cell ERG responses (p<0.01) in hA53T mice treated with L-DOPA grew more (147±9%) than WT mice (118±9%) treated with L-DOPA, which was similar in hA53T (125±7%) and WT (119±7%) mice treated with vehicle. OCT retinal thinning was found in outer retinal layers of hA53T mice [outer plexiform layer (OPL), outer nuclear layer (ONL), p<0.0001] which was not altered by L-DOPA treatment. This finding mirrored IHC and WB findings of elevated phosphorylated pS129 human α-syn levels (p<0.0001) localized to the ONL.
Conclusions :
Acute L-DOPA treatment temporarily improves visual dysfunction caused by abnormal α-synuclein accumulation. These findings provide a high-throughput framework primed for translation through which novel compounds can be screened, fast-tracking PD drug discovery.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.