Myeloid cells as mediators of glaucomatous axon self-destruction

University Of California At Davis, Davis CA

Investigators

Abstract

There are ongoing clinical trials premised on the idea that systemic treatments that increase Nicotinamide Adenine Dinucleotide (NAD+) will increase baseline metabolism within retinal ganglion cells (RGCs) which will make them more resilient to increases in intraocular pressure or other insults that might result in the characteristic pattern of axon and vision loss that defines glaucoma. However, much of our understanding about how NAD+ mediates neuroprotection derives originally from studies of Wallerian Degeneration Slow (WldS) mice, which after traumatic injuries have not only a ten-fold delay in axonal degeneration but also greatly delayed inflammation. Very recently, using a novel optic nerve crush (ONC) model in young Xenopus laevis (X. laevis) tadpoles, we reproduced the strong axon protective effect of the NAD+ boosting interventions and similarly found a large inhibition of myeloid cell recruitment to both the optic nerve and the main brain innervation target of RGCs. However, we then demonstrated that pharmacogenetic ablation of myeloid cells fully recapitulates the axon preservation afforded by the NAD+ boosting interventions. Our studies thus suggest that at least some of the neuroprotection afforded by NAD+ boosting interventions may be due to their anti-inflammatory activity. Here, we will determine whether NAD+ based interventions also work in a less traumatic, more glaucoma relevant, novel axon injury model that is based on conditional expression in RGCs of a rare glaucoma-associated Optineurin (OPTN) variant that produces extensive axonal loss. We will characterize the immune reaction in this model and determine whether immune cells are similarly consequential to the axonal degeneration. And then, using another novel axon degeneration model based on conditional expression in RGCs of a constitutively active form of the NAD+ catabolic enzyme Sterile Alpha and toll/interleukin-1 resistance (TIR) motif containing 1 (Sarm1), we will directly test the hypothesis that the timing of axon destruction due to NAD+ consumption within RGC axons in vivo is necessarily dependent on the consequent immune invasion. We will also test a corollary hypothesis, namely that injured axons damage healthy axons through the immune cells they recruit. In the process of answering these mechanistic questions about how axons may be damaged in glaucoma, this proposal will develop and characterize two novel axon injury models that we hope to use in the near future for large-scale genetic and pharmacological screens.