title: A role for vascular deficiency in retinal pathology in a mouse model of ataxia-telangiectasia.
abstract: Ataxia-telangiectasia is a multifaceted syndrome caused by null mutations in the ATM gene, which encodes the protein kinase ATM, a key participant in the DNA damage response. Retinal neurons are highly susceptible to DNA damage because they are terminally differentiated and have the highest metabolic activity in the central nervous system. In this study, we characterized the retina in young and aged Atm-deficient mice (Atm(-/-)). At 2 months of age, angiography revealed faint retinal vasculature in Atm(-/-) animals relative to wild-type controls. This finding was accompanied by increased expression of vascular endothelial growth factor protein and mRNA. Fibrinogen, generally absent from wild-type retinal tissue, was evident in Atm(-/-) retinas, whereas mRNA of the tight junction protein occludin was significantly decreased. Immunohistochemistry labeling for occludin in 6-month-old mice showed that this decrease persists in advanced stages of the disease. Concurrently, we noticed vascular leakage in Atm(-/-) retinas. Labeling for glial fibrillary acidic protein demonstrated morphological alterations in glial cells in Atm(-/-) retinas. Electroretinographic examination revealed amplitude aberrations in 2-month-old Atm(-/-) mice, which progressed to significant functional deficits in the older mice. These results suggest that impaired vascularization and astrocyte-endothelial cell interactions in the central nervous system play an important role in the etiology of ataxia-telangiectasia and that vascular abnormalities may underlie or aggravate neurodegeneration.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Raz-Prag
authors.forename: Ronit
authors.initials: R
authors.lastname: Galron
authors.forename: Niva
authors.initials: N
authors.lastname: Segev-Amzaleg
authors.forename: Arieh S
authors.initials: AS
authors.lastname: Solomon
authors.forename: Yosef
authors.initials: Y
authors.lastname: Shiloh
authors.forename: Ari
authors.initials: A
authors.lastname: Barzilai
authors.forename: Dan
authors.initials: D
authors.lastname: Frenkel
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001260:Ataxia Telangiectasia / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004596:Electroretinography; D004730:Endothelium, Vascular / Q000502:physiology; D051379:Mice; D012164:Retinal Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D012166:Retinal Hemorrhage / Q000473:pathology; D019108:Tight Junctions / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A