Role of PKN1 in retinal development and degeneration

Worldwide, 39 million people are blind and 285 million are vision-impaired. The main cause of incurable loss of vision, as it happens in glaucoma, diabetic retinopathy and ischemic neuropathy, lies in a permanent loss of retinal ganglion cells, the cells that give rise to the optic nerve and link the eye to the brain. A complete understanding of the developmental processes regulating the correct eye-brain connection is fundamental for the development of therapies that aim to restore vision. We have recently described a novel pathway that controls the correct neuronal wiring during cerebellar development. We showed that Protein kinase N1 (PKN1) inhibits the pro-survival protein AKT and subsequently results in a reduction of the transcription factor neuronal differentiation 2 (NeuroD2), which prevents maturation of neuronal connections. The proposed project Role of PKN1 in retinal development and degeneration will be dedicated to the analysis of this novel axis in the development of the visual pathway and its role in acute cellular stress-induced loss of retinal ganglion cells, as it happens during neuropathies. The project is based on our findings that mice lacking Pkn1 exhibit a defective growth of optic nerve fibers, show a reduction of certain retinal ganglion cell subtypes and subsequently have severe visual defects. I will use wildtype mice and mice lacking Pkn1 and study if there is a causal role of Pkn1 knockout and AKT/NeuroD2 hyperactivation that results in an altered development of retinal cell classes (objective 1) and a defective eye-brain connection (objective 2). This will be achieved by histological and electrophysiological analysis of retinas and brains and will be verified by behavioral tests. Attempts to regenerate the optic nerve currently fail to direct the nerve fiber growth in a way that restores spatial vision. Hence, results from this part of the project will provide fundamental new knowledge for the challenging task of re-establishing a functioning eye- brain connection after optic nerve damage or retinal ganglion cell loss. Additionally, based on its negative regulation of the pro-survival kinase AKT, inhibition of PKN1 might offer a new means to enhance neuronal survival during pathological conditions. Therefore, I will test if inhibition of PKN1 in adult wildtype animals suffering from stress-induced retinal ganglion cell loss is a novel approach to improve the survival of these cells and subsequently vision (objective 3). I will use clinically approved PKN1 inhibitors that have been validated for safe use in humans. The results of Objective 3 have the potential to open up new opportunities to protect against retinal ganglion cell loss in diseases such as glaucoma or ischemic neuropathy, and could be adapted for safe use in clinical trials.