Divergent redox responses of macular and peripheral Müller Glia: Implications for retinal vulnerability

Abstract

The macula is preferentially affected in some common retinal diseases (such as age-related macular degeneration, diabetic retinopathy and macular telangiectasia type 2), whereas most inherited retinal degenerations (e.g., retinitis pigmentosa) tend to initially affect the peripheral retina. This pattern suggests the macula may have intrinsic vulnerabilities in its oxidative stress defences, compared to the periphery. Profiling of single-cell level transcriptional changes found that the peripheral retina exhibited greater transcriptional alterations than the macula in response to stress. One pronounced change was in a subgroup of Müller glia (MG) that was dominant in the peripheral retina. Genes more abundantly expressed in peripheral MG were mainly associated with redox regulation, oxidative stress responses and cellular detoxification and were more influenced by oxidative insults, such as light-induced stress. In contrast, genes highly expressed in macular MG were primarily involved in cellular homeostasis and neuroprotection, showing less responsiveness to oxidative challenges. Notably, Metallothionein 1 (MT1), A-Kinase Anchor Protein 12 (AKAP12) and MAF BZIP Transcription Factor F (MAFF) were significantly more expressed in peripheral MG than in macular MG, indicating a region-specific redox regulatory mechanism. Knockdown of these genes in primary MG led to decreased viability under oxidative stress, suggesting their role in antioxidant defence. Our findings indicate that macular MG prioritise retinal function over redox adaptation, which may contribute to their vulnerability to degenerative diseases associated with oxidative damage. These insights underscore the importance of region-specific redox homeostasis in retinal health and disease.