GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target

Glycogen synthase kinase 3 (GSK3) is a key regulator of many cellular signaling processes and performs a wide range of biological functions in the nervous system. Due to its central role in numerous cellular processes involved in cell degeneration, a rising number of studies have highlighted the interest in developing therapeutics targeting GSK3 to treat neurodegenerative diseases. Although recent works strongly suggest that inhibiting GSK3 might also be a promising therapeutic approach for retinal degenerative diseases, its full potential is still under-evaluated. In this review, we summarize the literature on the role of GSK3 on the main cellular functions reported as deregulated during retinal degeneration, such as glucose homeostasis which is critical for photoreceptor survival, or oxidative stress, a major component of retinal degeneration. We also discuss the interest in targeting GSK3 for its beneficial effects on inflammation, for reducing neovascularization that occurs in some retinal dystrophies, or for cell-based therapy by enhancing Muller glia cell proliferation in diseased retina. Together, although GSK3 inhibitors hold promise as therapeutic agents, we highlight the complexity of targeting such a multitasked kinase and the need to increase our knowledge of the impact of reducing GSK3 activity on these multiple cellular pathways and biological processes.