Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma

Abstract

In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve crosssection were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of~18.5 (p genome-wide~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including Gpnmb, Tyrp1, Cdh11, Pou6f2, and Cacna2d1. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-CDC42 binding protein kinase beta (Cdc42bpb); eukaryotic translation initiation factor 5 (Eif5); BCL2-associated athanogene 5 (Bag5); apoptogenic 1, mitochondrial (Apopt1); kinesin light chain 1 (Klc1); X-ray repair cross complementing 3 (Xrcc3); protein phosphatase 1, regulatory subunit 13B (Ppp1r13b); and transmembrane protein 179 (Tmem179)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.

Pathologically high intraocular pressure disturbs normal iron homeostasis and leads to retinal ganglion cell ferroptosis in glaucoma

“…The mechanisms underlying RGC injury during ph-IOP include: (1) Mechanical pressure on the optic disc and lamina cribrosa, which distorts the fovea, compresses RGC axons, and blocks axoplasmic transport, resulting in the activation of apoptotic and necrotic pathways; (2) decreased retinal blood perfusion, resulting in RGC ischemic injury; (3) activation of immune responses, leading to inflammatory cell infiltration that injures RGCs; and (4) other potential mechanisms [ 5 – 7 ]. Effective clinical options are limited, and current glaucoma treatments aim to lower ph-IOP using medications or surgery [ 8 ].…”

Identification of hub genes for glaucoma: a study based on bioinformatics analysis and experimental verification

“…In the MF category, the DEGs primarily associated with protein kinase binding, protein serine/threonine kinase activity and metal ion binding. The previous study has shown that CDC42 binding protein kinase beta is associated with changes in the number of necrotic axons in the optic nerve [27] . Rho kinase, a serine/threonine protein kinase, its inhibitors reduce IOP in vivo and in vitro [28] .…”

Locus specific endogenous retroviral expression associated with Alzheimer’s disease

“…The sequence is located on human 14q32.33, which has previously been identified as a potential evolutionary breakpoint ( Ruiz-Herrera et al, 2006 ; Longo et al, 2009 ). This protein has recently been identified as one of eight probable modulators of optic nerve necrosis in mice ( Stiemke et al, 2020 ). It has also been demonstrated that TMEM179 is expressed in oligodendrocyte precursor cells (OPCs), astrocytes, and neurons; and that it is found in the cortex, hippocampus, and hypothalamus of mice ( He et al, 2021 ).…”