Here is again a new eye paper by Dr. Nquyen and Prof Finkelstein demonstrating alpha-synuclein interaction in the retina, which provides a new screening tool for fast-tracking potential PD drugs. I would be almost sure that they have tested ATH434 in this model at least in the primate study but maybe many other molecules ATH has patented. A very speedy method of testing potential new drugs.

Biomedicines

. 2024 Jan 8;12(1):130.

doi: 10.3390/biomedicines12010130.

Levodopa Rescues Retinal Function in the Transgenic A53T Alpha-Synuclein Model of Parkinson's Disease

Katie K N Tran ¹, Vickie H Y Wong ¹, Kirstan A Vessey ², David I Finkelstein ³, Bang V Bui ¹, Christine T O Nguyen ¹

Affiliations expand

• PMID: 38255235

DOI: 10.3390/biomedicines12010130

Abstract

Background: Loss of substantia nigra dopaminergic cells and alpha-synuclein (α-syn)-rich intraneuronal deposits within the central nervous system are key hallmarks of Parkinson's disease (PD). Levodopa (L-DOPA) is the current gold-standard treatment for PD. This study aimed to evaluate in vivo retinal changes in a transgenic PD model of α-syn overexpression and the effect of acute levodopa (L-DOPA) treatment.

Methods: Anaesthetised 6-month-old mice expressing human A53T alpha-synuclein (HOM) and wildtype (WT) control littermates were intraperitoneally given 20 mg/kg L-DOPA (50 mg levodopa, 2.5 mg benserazide) or vehicle saline (n = 11-18 per group). In vivo retinal function (dark-adapted full-field ERG) and structure (optical coherence tomography, OCT) were recorded before and after drug treatment for 30 min. Ex vivo immunohistochemistry (IHC) on flat-mounted retina was conducted to assess tyrosine hydroxylase (TH) positive cell counts (n = 7-8 per group).

Results: We found that photoreceptor (a-wave) and bipolar cell (b-wave) ERG responses (p < 0.01) in A53T HOM mice treated with L-DOPA grew in amplitude more (47 ± 9%) than WT mice (16 ± 9%) treated with L-DOPA, which was similar to the vehicle group (A53T HOM 25 ± 9%; WT 19 ± 7%). While outer retinal thinning (outer nuclear layer, ONL, and outer plexiform layer, OPL) was confirmed in A53T HOM mice (p < 0.01), L-DOPA did not have an ameliorative effect on retinal layer thickness. These findings were observed in the absence of changes to the number of TH-positive amacrine cells across experiment groups. Acute L-DOPA treatment transiently improves visual dysfunction caused by abnormal alpha-synuclein accumulation.

Conclusions: These findings deepen our understanding of dopamine and alpha-synuclein interactions in the retina and provide a high-throughput preclinical framework, primed for translation, through which novel therapeutic compounds can be objectively screened and assessed for fast-tracking PD drug discovery.