Differential up-regulation of Vesl-1/Homer 1 protein isoforms associated with decline in visual performance in a preclinical glaucoma model.
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.
Vision Research Center, Department Ophthalmology, University of Missouri - Kansas City, School of Medicine, Kansas City, MO 64108, United States. Electronic address: kajas@umkc.edu.
Simon
S
Kaja
Vision Research Center, Department Ophthalmology, University of Missouri - Kansas City, School of Medicine, Kansas City, MO 64108, United States.
Yuliya
Y
Naumchuk
Vision Research Center, Department Ophthalmology, University of Missouri - Kansas City, School of Medicine, Kansas City, MO 64108, United States.
Stephanie L
SL
Grillo
Vision Research Center, Department Ophthalmology, University of Missouri - Kansas City, School of Medicine, Kansas City, MO 64108, United States.
Priscilla K
PK
Borden
Vision Research Center, Department Ophthalmology, University of Missouri - Kansas City, School of Medicine, Kansas City, MO 64108, United States; Department of Basic Medical Science, University of Missouri - Kansas City, School of Medicine, Kansas City, MO 64108, United States.
Peter
P
Koulen
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D015350:Contrast Sensitivity / Q000502:physiology*; D004195:Disease Models, Animal; D005901:Glaucoma / Q000378:metabolism* / Q000503:physiopathology; D000072233:Homer Scaffolding Proteins; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D020033:Protein Isoforms / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D012684:Sensory Thresholds / Q000502:physiology; D015854:Up-Regulation; D014792:Visual Acuity / Q000502:physiology*
D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D020033:Protein Isoforms
Calcium channel; DBA/2J; Glaucoma; HRP; IOP; Neurodegeneration; RGCs; Synaptic clustering; VASP/Ena-related gene up-regulated during seizure and LTP protein; Vesl; Vesl/Homer; horseradish peroxidase; intraocular pressure; retinal ganglion cells