RIP Kinases, necroptosis and redundancy in neuronal cell death

Abstract

AbstractPurpose Neuronal cell death is the major cause of vision loss in many eye diseases. The exact mechanism remains unknown. Apoptosis has been thought to be the major form of regulated cell death and the main modality of neuronal cell death in degenerative ailments. However, neuroprotective strategies based on apoptosis have failed to materialize. We wanted to investigate the presence of alternative cell death modalities in various models of degenerative eye diseases.Methods Neuronal cell death was studied in a variety of animal models, including retinal detachment, RD10 juvenile degeneration, Cx3Cr1/CCL2/rd8 triple mutant, optic nerve crush, and chemical toxicity models (NMDA, PolyI:C, Na‐Iodate, Lipid peroxide, and chloroquine). Analysis of cell death was performed by transmission electron microscopy (TEM), TUNEL staining and standard molecular techniques.Results Caspase dependent apoptosis was the major cell death modality in most models of cell degeneration. However, RIP regulated necrosis accounted for a significant portion of cell death morphology. Under conditions of selective caspase inhibition, RIP regulated necrosis became the predominant cell death modality. Simultaneous caspase and RIPK inhibition lead to significant neuroprotection. Autophagy accounted for small portion of cell death in the models that it was examined.Conclusion RIP Kinase regulated necrosis (necroptosis) is a significant redundant cell death pathway in many animal models of ocular degenerative diseases. It becomes the predominant form of cell death under conditions of caspase inhibition. Combination treatments may be needed for successful neuroprotection. Commercial interest