Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model

Abstract

Glaucoma is a multifactorial progressive ocular pathology, clinically presenting with damage to the retina and optic nerve, ultimately leading to blindness. Retinal ganglion cell loss in glaucoma ultimately results in vision loss. Vesl/Homer proteins are scaffolding proteins that are critical for maintaining synaptic integrity by clustering, organizing and functionally regulating synaptic proteins. Current anti-glaucoma therapies target IOP as the sole modifiable clinical parameters. Long-term pharmacotherapy and surgical treatment do not prevent gradual visual field loss as the disease progresses, highlighting the need for new complementary, alternative and comprehensive treatment approaches. Vesl/Homer expression was measured in the retinae of DBA/2J mice, a preclinical genetic glaucoma model with spontaneous mutations resulting in a phenotype reminiscent of chronic human pigmentary glaucoma. Vesl/Homer proteins were differentially expressed in the aged, glaucomatous DBA/2J retina, both at the transcriptional and translational level. Immunoreactivity for the long Vesl-1L/Homer 1c isoform, but not of the immediate early gene product Vesl-1S/Homer 1a was increased in the synaptic layers of the retina. This increased protein level of Vesl-1L/Homer 1c was correlated with phenotypes of increased disease severity and a decrease in visual performance. The increased expression of Vesl-1L/Homer 1c in the glaucomatous retina likely results in increased intracellular Ca2+ release through enhancement of synaptic coupling. The ensuing Ca2+ toxicity may thus activate neurodegenerative pathways and lead to the progressive loss of synaptic function in glaucoma. Our data suggest that higher levels of Vesl-1L/Homer 1c generate a more severe disease phenotype and may represent a viable target for therapy development.

Upregulation of Homer1a Promoted Retinal Ganglion Cell Survival After Retinal Ischemia and Reperfusion via Interacting with Erk Pathway

“…Homer signaling plays important roles in the pathogenesis of ocular diseases and other neurological disorders, such as TBI (Luo et al 2012b;Menard and Quirion 2012;Kaja et al 2014). In this study, we observed that the expression of Homer1a protein was significantly elevated in primary cultured RGCs after OGD injury and in the retinas subjected to I/R injury, consistent with our previous study involving TBI (Luo et al 2014).…”

“…In this study, we observed that the expression of Homer1a protein was significantly elevated in primary cultured RGCs after OGD injury and in the retinas subjected to I/R injury, consistent with our previous study involving TBI (Luo et al 2014). Our results were partially inconsistent with those of Kaja et al, who found no significant difference between Homer1a expression in the retinas from 9-month-old DBA/2J mice and 6-week old DBA/2J mice, but Homer 1a was moderately correlated with IOP (Kaja et al 2014). The inconsistency of Homer1a expression might partially be attributed to different models and observation times.…”

“…Furthermore, related studies suggest that Homer1a was highly expressed in a premature stage and gradually declined with aging, suggesting that the expression of Homer1a was age-specific in the development of the nervous system (Bek et al 2009;Colucciello 2004;Kammermeier and Worley 2007;Kaja et al 2003). The age-specific expression may partially explain the non-significant difference in the increase of Homer1a expression between 9 months and 6 weeks in glaucomatous DBA/2J mice (Kaja et al 2014).…”

“…Additionally, the different stages of the disease may also have contributed to the inconsistencies. For instance, different levels of Homer1a expression may occur in the acute and chronic stages of the disease (Kaja et al 2014). Furthermore, related studies suggest that Homer1a was highly expressed in a premature stage and gradually declined with aging, suggesting that the expression of Homer1a was age-specific in the development of the nervous system (Bek et al 2009;Colucciello 2004;Kammermeier and Worley 2007;Kaja et al 2003).…”

“…However, the underlying mechanisms of protection including the interaction of Homer1a with Erk, and additional detailed mechanisms mediating RGCs I/R injury need further elucidation (Duncan et al 2005;Hwang et al 2003;Tanaka et al 2006;Westhoff et al 2003;Kaja et al 2014).…”