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Introduction Alongside Alzheimer's disease, Parkinson's disease (PD) and age-related macular degeneration (AMD) are the most common age-associated neurodegenerative diseases (1, 2). AMD is the leading cause of central vision loss [...], Neovascular age-related macular degeneration (nAMD) remains a major cause of visual impairment and puts considerable burden on patients and health care systems. L-DOPA-treated Parkinson's disease (PD) patients have been shown to be partially protected from nAMD, but the mechanism remains unknown. Using murine models that combine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP-induced) PD and laser-induced nAMD with standard PD treatment of L-DOPA/DOPA-decarboxylase inhibitor or specific dopamine receptor inhibitors, we here demonstrate that L-DOPA treatment-induced increase of dopamine-mediated dopamine receptor D2 (DRD2) signaling inhibits choroidal neovascularization independently of MPTP-associated nigrostriatal pathway lesion. Analyzing a retrospective cohort of more than 200,000 patients with nAMD receiving anti-VEGF treatment from the French nationwide insurance database, we show that DRD2 agonist-treated PD patients have a significantly delayed age of onset of nAMD and reduced need for anti-VEGF therapies, similar to the effects of the L-DOPA treatment. While providing a mechanistic explanation for an intriguing epidemiological observation, our findings suggest that systemic DRD2 agonists might constitute an adjuvant therapy to delay and reduce the need for anti-VEGF therapy in patients with nAMD.

An animal model of Leber Hereditary Optic Neuropathy (LHON) is developed and employed for an effective optimization of the allotopic expression of the ATP6, ND1 and ND4 mitochondrial genes in humans. Such an optimization of the expression is shown to be extremely effective for the treatment of the rat model.

Orthodenticle homeobox 2 ( OTX2) controls essential, homeostatic retinal pigment epithelial ( RPE) genes in the adult. Using cocultures of human CD14+ blood monocytes (Mos) and primary porcine RPE cells and a fully humanized system using human-induced pluripotent stem cell-derived RPE cells, we show that activated Mos markedly inhibit RPE OTX2 expression and resist elimination in contact with the immunosuppressive RPE. Mechanistically, we demonstrate that TNF-α, secreted from activated Mos, mediates the downregulation of OTX2 and essential RPE genes of the visual cycle among others. Our data show how subretinal, chronic inflammation and in particular TNF-α can affect RPE function, which might contribute to the visual dysfunctions in diseases such as age-related macular degeneration ( AMD) where subretinal macrophages are observed. Our findings provide important mechanistic insights into the regulation of OTX2 under inflammatory conditions. Therapeutic restoration of OTX2 expression might help revive RPE and visual function in retinal diseases such as AMD. [ABSTRACT FROM AUTHOR]