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


Authors: Kaja, S.; Naumchuk, Y.; Grillo, S. L.; Borden, P. K.; Koulen, P.
Article Title: 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 Ca(2+) release through enhancement of synaptic coupling. The ensuing Ca(2+) 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.
Journal Title: Vision research
Volume: 94
ISSN: 1878-5646; 0042-6989
Publisher: Elsevier Inc  
Journal Place: England
Date Published: 2014
Start Page: 16
End Page: 23
Language: ENG
DOI/URL:
Notes: LR: 20161019; CI: Copyright (c) 2013; GR: P01 AG022550/AG/NIA NIH HHS/United States; GR: P01 AG027956/AG/NIA NIH HHS/United States; GR: AG010485/AG/NIA NIH HHS/United States; GR: R01 EY014227/EY/NEI NIH HHS/United States; GR: AG022550/AG/NIA NIH HHS/United States; GR: P01 AG010485/AG/NIA NIH HHS/United States; GR: EY014227/EY/NEI NIH HHS/United States; GR: R01 EY022774/EY/NEI NIH HHS/United States; GR: EY022774/EY/NEI NIH HHS/United States; GR: RR022570/RR/NCRR NIH HHS/United States; GR: AG027956/AG/NIA NIH HHS/United States; GR: S10 RR027093/RR/NCRR NIH HHS/United States; GR: S10 RR022570/RR/NCRR NIH HHS/United States; GR: RR027093/RR/NCRR NIH HHS/United States; JID: 0417402; 0 (Carrier Proteins); 0 (Homer protein); 0 (Protein Isoforms); NIHMS541188; OID: NLM: NIHMS541188; OID: NLM: PMC3890355; OTO: NOTNLM; 2013/08/31 [received]; 2013/10/26 [revised]; 2013/10/28 [accepted]; ppublish