Upregulation of Gap Junction Connexins in Glaucoma

Abstract

Glaucoma is a leading cause of irreversible blindness, which is characterized by a progressive degeneration of the optic nerve and loss of retinal ganglion cells (RGCs). Glaucoma currently affects 3.5% of individuals aged 40 to 80 years, and the incidence of glaucoma is increasing together with life expectancies (Wagner et al., 2022). There is strong evidence that intercellular communication via gap junctions (GJs) facilitates secondary cell death, by means of the so-called “bystander effect” is which dying cells releases toxins that lead to the death of neighboring cells to which they are coupled (Akopian et al., 2014; 2017). Pharmacological blockade of GJs or genetic deletion of GJ subunit connexins Cx36 (Akopian et al., 2017) or Cx43 (Batsuuri et al., 2023) showed an increase in neuronal survivability by greater than 70% in glaucomatous retinas providing clear evidence that GJs can mediate secondary cell death, which can account for loss of most retinal neurons. Since Cx36 is expressed by GJs between retinal neurons and Cx43 is expressed between glial astrocytes, there are potentially two separate pathways that may underlie cell loss in glaucoma. This raises the important question of whether these pathways are independent mechanisms for cell death or are interdependent. Interestingly, both Cx36 and Cx43 are upregulated in glaucomatous retinas (Akopian et al., 2017; Batsuuri et al., 2023). Therefore, to assay the interdependence of bystander death mediated by Cx36- and Cx43-expressing GJs in glaucoma, we determined if their upregulation were interconnected. Understanding the potential interdependence of these two GJ-mediated bystander cell death pathways would help define potential targets for neuroprotection in glaucoma.